Assessing Steric Bulk of Protecting Groups Via a Computational Determination of Exact Cone Angle and Exact Solid Cone Angle

Home , Silyl ether

ASSESSING STERIC BULK OF PROTECTING GROUPS VIA A COMPUTATIONAL DETERMINATION OF EXACT CONE ANGLE (θo) AND EXACT SOLID CONE ANGLE (Θo)

A thesis submitted to the Kent State University Honors College in partial fulfillment of the requirements for General Honors

Julian Witold Sobieski

May, 2018

Thesis written by

Julian Witold Sobieski

Approved by

______, Advisor

______, Chair, Department of Chemistry and Biochemistry

Accepted by

______, Dean, Honors College

TABLE OF CONTENTS

LIST OF FIGURES ...... iv

LIST OF TABLES ...... v

LIST OF COMMON ABBREVIATIONS ...... vi

ACKNOWLEDGEMENTS ...... viii

CHAPTER

I. INTRODUCTION ...... 1

1.1: The need for organic protecting group steric descriptors ...... 1

1.2: The Tolman angle ...... 4

1.3: Exact cone angle (θo) and exact solid cone angle (Θo) ...... 6

1.4: Other literature methods for calculating steric bulk ...... 10

II. COMPUTATIONAL RESULTS ...... 14

2.1: Computational method ...... 14

2.2: Computed cone angles ...... 16

2.3: Protecting group symmetry ...... 20

2.4: Silyl protecting groups ...... 21

2.5: Constraints for conformations caused by intramolecular attractions..25

III. CONCLUSIONS ...... 28

REFERENCES ...... 30

APPENDIX ...... 33

iii

LIST OF FIGURES

Figure 1. Selective protection of a hydroxyl group using a trialkylsilyl triflate ...... 1

Figure 2. A PG-dependent unique synthetic step; synthesis of Tirandamycin exhibiting selectivity within the silyl ether orthogonal PG set ...... 2

Figure 3. A schematic definition of steric and electronic effects at an oxygen ...... 3

Figure 4. A depiction from the Mathematica software package FindConeAngle of calculating the exact cone angle for TMS ...... 7

Figure 5. The summation of shadow cones from substituent atoms of TES on the encompassing shell ...... 8

Figure 6. Schematic for obtaining the exact solid and exact cone angles of TMS ...... 14

Figure 7. The allyl anion α/γ problem ...... 22

Figure 8. Visualization of equilibrium-optimized TPS xyz coordinates using Mercury 3.8..23

Figure 9. Desired Mitsunobu reaction adduct from a systematic study of protecting group steric influence ...... 24

Figure 10. Examples of equilibrium-optimized 3-nitro-2-naphthylmethyl ...... 26

LIST OF TABLES

Table

1. Exact cone angles (θo) and exact solid cone angles (Θo) for 60 hydroxyl (O) and amine (N) protecting groups ...... 19

2. Silyl PG exact cone angles and exact solid cone angles, with analogous Tolman angle approximations ...... 22

3. Comparison of protecting groups undergoing intramolecular interactions before and after applying dihedral constraints. The ‘c’ subscript indicates the use of dihedral constraint approach ...... 25

LIST OF ABBREVIATIONS*

Ac – acetyl Alloc – allyloxycarbonyl Bn – benzyl BOC – tert-butoxycarbonyl BOM – benzyloxymethyl Bz – benzoyl Cbz – benzylocarbonyl DEIPS – diethyl-iso-propylsilyl DMB – 3,4-dimethoxybenzyl EE – 2-ethoxyethyl Fmoc – 9-fluorenylmethoxycarbonyl IPDMS – ipropyldimethylsilyl Me – methyl MEM – 2-methoxyethoxymethyl MME – 1-methoxy-1-methylethyl MOM – methoxymethyl MTM – methylthiomethyl NAP – 2-napthylmethyl Noc – p-nitrocinnamyloxycarbonyl Nps – o-nitrophenylsulfenyl PG – protecting group Ph – phenyl vi

PhFl – 9-phenyl-9-fluorenyl pixyl – 9-phenyl-9-xanthenyl PMP – p-methoxyphenyl PMB – p-methoxybenzyl PNB – p-nitrobenzyl PPG – photoremovable protecting group Psec – 2-phenylsulfonylethylcarbonyl Pv – pivaloyl TBDMS – tert-butyldimethylsilyl TBDPS – tert-butyldiphenylsilyl TDS – thexyldimethylsilyl THP – tetrahydropyran-2-yl Troc – 2,2,2-trichloroethoxycarbonyl Tsoc – triisopropylsilyloxycarbonyl

*Protecting group naming conventions taken from Kocienski1

vii

ACKNOWLEDGMENTS

First and foremost I thank Dr. Scott Bunge for his guidance and support during this thesis and the last three years as advisor, instructor, mentor, and friend. I thank my parents and sisters for helping and encouraging me to pursue academics. I also thank Dr. Mitch

Lambert, Mr. David Killius, and Mr. Benjamin Marquette for their gifted of chemistry and physics.

I would like to thank the members of the defense committee for their time and expertise. A special thank you to Dr. Mietek Jaroniec for being my first research advisor, continuously supporting me in my academic career, and being on the defense committee.

Another special thank you to Dr. Paul Sampson for his undergraduate advising, gifted teaching of organic chemistry, help in editing this work, and presence on the defense committee. I thank Dr. Paul Sampson, Dr. Alexander Seed, and Mark Campbell for motivating this work.

viii

CHAPTER I

INTRODUCTION

Section 1.1: The need for organic protecting group steric descriptors

The steric bulk of organic protecting groups (PG) are of interest to chemists because the steric effect mediates reactions by affecting accessibility of reaction sites, kinetics, molecular conformation, and transition states2-5. The purpose of a PG is to temporarily render a functional group inert by appending a group that can be later removed. These groups are classified under PG “orthogonal sets” whose deprotection modes do not affect

1 PGs in other orthogonal sets . For example, the formation of a trialkylsilyl ether (-OSiR3) as reported by Heathcock et al. can selectively protect hydroxyl groups6.

Figure 1: Selective protection of a hydroxyl group using a trialkylsilyl triflate.

The selective deprotection of trialkylsilyl ethers is motivated by the high affinity of Si for fluorine. For example, the synthesis of Tirandamycin utilizes contingent removal of silyl ethers using aqueous HF and catalytic fluorosilicic acid (H2SiF6) depending on the reaction

time, as subsequent studies by the same group report that TBDMS, TIPS, and TBDPS ethers can be removed in reaction times of 20 min, 20 h, and 5 days, respectively7-8. Other acid-labile groups such as THP, MEM, and acetonides survive these conditions1.

Furthermore, selective deprotection of TBDMS and acetalization motivate the ring- formation seen in Figure 2.

Figure 2: A PG-dependent unique synthetic step: synthesis of Tirandamycin exhibiting selectivity within the silyl ether orthogonal PG set.

Despite the widespread use of PGs with significant variation in structure, there have been few attempts at precisely calculating steric bulk9. Due to the lack of a comprehensive set of steric descriptors for PGs, it is of interest to develop a method for calculating PG steric descriptors because of the importance of steric influence in mediating reactions. The descriptors may subsequently provide insight to synthetic phenomena. Ideally, the developed method should calculate steric descriptors of PGs and satisfy the following three criteria: (i) accommodate any functionality, size, or complexity; (ii) model its native

behavior as best as possible; and (iii) analyze compounds that cannot be easily structurally characterized utilizing alternative approaches.

Protecting groups in organic syntheses are selected for their electronic and steric properties (Figure 3). Electronics for hydroxyl and amine PGs, which have been thoroughly researched in comparison to sterics, play a critical role in chemoselectivity2. However, an equally common use of PGs is to mediate regioselectivity and reaction kinetics through steric bulk9.

Figure 3: A schematic definition of steric and electronic effects at an oxygen (red).

But, quantified steric parameters for organic PGs are rarely included in the discussion of protecting groups. An efficient and comprehensive method for calculating the steric bulk of organic PGs is necessary to complete the chemoselectivity and regioselectivity reasoning used for selecting a suitable PG for synthesis.

In general, it is preferable to avoid using organic protecting altogether due to the inherent costs and time of adding a protection and deprotection step into syntheses1.

Theoretically, once organic synthesis is mastered, PGs could become obsolete. However, many polyfunctional molecules are so complex that PGs are unavoidable in the scope of

today’s organic synthetic theory. Furthermore, PGs themselves can unlock synthetic pathways that are unique, an example being the α/γ allyl anion problem9-10. Therefore, the usefulness of organic PGs is not likely to ever completely disappear.

Section 1.2: The Tolman angle

The Tolman angle θ, also known as the ligand cone angle, was published in 1976 to describe the steric effect that organic ligands have on the reactivity of metal centers11.

Invented as a steric descriptor for explaining the competition of phosphorous ligands coordinating to Ni(0), θ is calculated by forming a cone with the outermost atoms of the ligand and the metal center as the vertex. In 1995, the Tolman angle was used as one of the first cone angle approximations for the organosilyl family of organic PGs using analogous nickel phosphines9, 12-13. For example, the cone angle of TMS was assumed to be the

Tolman angle of trimethylphosphine. In the review of the TIPS PG, Ruecker grounds his reasoning for approximating organosilyls as organophospines by the proximities of silicon and phosphorous on the periodic table. This approximation is ingenious in its simplicity and application, but suffers from the inaccuracies of the Tolman angle, even before considering spatial or conformational differences between analogous organosilanes and organophosphines. We will see that bulkier organic substituents R, such as phenyl rings, are susceptible to energy-minimized conformations of the Si-R dihedral angle; the Tolman angle cannot innately account for this impactful factor of calculating the cone angle.

In symmetrical nickel-phosphines, θ is two times the half-angle of one substituent. For the Tolman angle to adequately quantify the steric bulk of organic PGs, it is necessary to

account for asymmetrical PG substituents. When expanded to asymmetrical nickel- phosphines, the model minimizes the sum of half-angles shown in eq. 1:

θ = (2/3) Σi=1,2,3 θi/2 (1),

where θi/2 is the half-angle of the i-th phosphine substituent on the tetrahedral phosphine.

Since the Tolman angle has traditionally been applied to phosphine ligands, calculations empirically set the metal-phosphorous bond length to be 2.28 Å, which is the distance of a

Ni-P bond. However, real metal-phosphorous covalent radii vary from 2.12 Å to 2.55 Å.

Varying metal covalent radii are an inherent difficulty to comprehensively calculating cone angles and ligand shadows, as the radii affects the proximity of the outermost atoms of the ligand and therefore the cone angle.

For calculating the exact cone angle and solid cone angle of organic PGs, a metal covalent radius is assumed to be fixed, just as in the Tolman angle. However, organic PGs are generally constrained to only the distance of an O-PG or N-PG bond length, which can be considered constant within their respective families of PGs. Thus, Tolman’s reasoning is actually better applied for organic PGs than metal-ligands; the 2.28 Å assumption can overestimate the cone angle for more distant ligands and underestimate for more proximate ligands. However, for organic PGs, the covalent radii and bond-lengths are similar within a set. When calculating the cone angle of an organic PG, the vertex atom of the calculation can therefore be arbitrarily chosen. The vertex atom element type is only required to be held constant through all calculations and the element should exhibit no significant

additional interaction with the PG other than the primary coordination mode. For all the cone angle calculations in this work, palladium was chosen to be the vertex atom.

Section 1.3: Exact cone angle (θo) and exact solid cone angle (Θo)

The exact cone angle (θo) and exact solid cone angle (Θo) are successors to the Tolman angle for calculating metal-ligand steric bulk that we believe should be applied to organic

PGs as the primary references for steric bulk. The exact cone angle is a mathematically rigorous estimation of the cone angle by solving for the most acute right circular cone. The

‘exact’ prefix denotes an improved, mathematically rigorous analytical solution proposed by Bilbrey, the mathematical formulation of which far exceeds the scope of this work14-15.

For ligands, the most acute right circular cone is created by rotating the metal-ligand complex about the axis of the metal-ligand bond. The outermost surface of the outermost atom carves out a space with a defined angle from the axis of rotation (Figure 4).

The same fundamental operation can be applied to organic PGs, except the axis of rotation is a bond between the vertex atom and the covalent singly-bonded PG. The vertex atom is the point at which the cone converges. The outermost surface(s) of the outermost substituent atom(s) trace a cone when the PG is rotated by being at a fixed distance from the axis of rotation about the vertex bond. The rotation creates the cone of the greatest angle at the vertex. In the case of TMS, the outermost point of contact is seen between a hydrogen of the methyl and the cone (Figure 4). The calculation of θo is proper for TMS, as it is a singly-bonded organic PG that is naturally rotationally free.

Figure 4: A depiction from the Mathematica software package FindConeAngle of calculating the exact cone angle for TMS14; vertex atom = Pd (space-filling Pd atom not shown); grey = Si, light grey = C, white = H.

The exact solid cone angle (Θo) is most easily understood as the rotationally-frozen analog of θo and an analytical improvement to the previously known solid cone angle (Θ).

If the exact cone angle is the maximum measurement of a substituents steric influence through rotational freedom, then the exact solid cone angle represents a substituent’s minimum steric influence through rotational freezing. Whereas the exact cone angle utilizes a rotation of the ligand about its axis of the vertex atom-ligand bond, the solid cone angle encompasses the metal-ligand complex in a spherical shell with the metal at the origin and the ligand rotationally frozen. The vertex atom is replaced with a “virtual” point light-

source that illuminates the shell from inside. However, spherical ligand atoms block the light and create a series of shadow cones that overlap and imprint a total shadow.

Figure 5: The summation of shadow cones (grey) from substituent atoms of TES on the encompassing shell (yellow). Larger circles are shadows are from Si and C, while smaller circles are shadows from H.

Bilbrey defines the solid cone angle as

Θ ≡ 2 cos-1(1-Ω/2π) (2),

where Ω is the solid angle of the complete shadow cast by a ligand if hypothetically illuminated from the metal center. Fundamentally, the exact solid cone angle Θo and solid cone angle Θ parameters are the same, except the former utilizes a mathematically improved parameter called the exact ligand solid angle Ωo in place of ligand solid angle Ω.

The greatest difficulty with the solid cone angle method is that of shadow redundancy; the

overlap of multiple shadows in a single area has not had an analytical solution appear in literature14. In the 1990s, algorithms were devised to reduce errors in Ω due to overlapping shadows. In any case, if an approximate Ω is obtained, equation 2 can be used. However, the more exact parameter Ωo is a line integral around the multisegmented perimeter of the ligand shadow, and does not depend on problematic ligand solid angle integration15. In

Figure 5, shadow cones that contribute to the total shadow are shown. The fundamental concept remains the same, however, in that virtual illumination is casted outwards from the vertex atom, and the resulting shadow cones from constituent atoms are summed on an encompassing sphere as the ligand shadow. Bilbrey’s work focuses on ligands complexed to Pd, Ni, and Pt, but there is reasoning for why the same approach can be used for organic

PGs bonded to a palladium in place of a vertex oxygen or nitrogen.

Bilbrey’s method uses a theoretical energy-minimized approximation of the metal- ligand molecule, from which the atomic coordinates are compiled in an XYZ (XMol) format. These coordinates are plugged into the Mathematica packages FindConeAngle and

FindSolidAngle to obtain the exact cone angle and solid cone angle of the ligand for a given metal center14-16. Using the same method but tailoring the ligand to be organic PGs, a comprehensive series of steric bulk calculations for organic PGs can theoretically be constructed.

However, FindConeAngle and FindSolidAngle drivers reject XYZ files with what we approximate to be an interatomic distance < 2.0 Å between vertex atom and subsequent PG atom. For metal-ligand complexes, the interatomic distance between metal (vertex atom) and subsequent atom is rarely < 2.0 Å; the converse is true for organic PGs in their native

environment. Thus, Bilbrey’s method has not been applied to organic PGs, until now.

Building upon the work of Tolman and Ruecker, a novel approach for the calculation of steric bulk for organic PGs will be undertaken.

A standardized vertex atom, chosen to be Pd for comparison to Bilbrey’s calculations and Pd’s propensity to have low coordination numbers, is bonded to a PG moiety that typically would be bonded to oxygen or nitrogen. An energy-minimized structure is then determined15, 17. In this work, this approach is referred to as the Pd-PG method and is more versatile than using Cartesian coordinates obtained from traditional crystallographic methods. Since it is a theoretical in nature, the Pd-PG method is impervious to packing factors found when utilizing solid-state structural data.

Section 1.4: Other literature methods for calculating steric bulk

All current methods for determining steric descriptors of ligands or PGs that could be used for determining cone angles of PGs suffer from failing to comprehensively accommodate complex PGs.

Concerning the steric bulk of organic substituents, no discussion would be complete without the Taft parameter ES. First published in 1956, ES is considered a fundamental breakthrough in defining steric parameters18. Taft’s parameter uses an averaging of reactivity data for four closely-related acid- and base-catalyzed hydrolysis/esterification reactions of carboxylic esters. However, discrepancy on whether averaging procedures mask minor electronic effects and whether all four reactions provide identical responses to steric effects led to the creation of the revised Taft-Dubois steric parameter E’S. The revised

Taft-Dubois parameter utilizes the rate of acid-catalyzed esterification of acetic acid in methanol at 40 oC for

E’S = log (k/ko) (3)

as a single reference ko to the rate k of the analogous esterification using the alkyl being tested as a carboxylic acid. Despite the simplification proposed by Dubois et al, the Taft-

Dubois steric parameter is not an ideal candidate for quantifying the steric bulk of PGs because it mainly, if not only, applies to open chain alkyl groups, and PGs vary greatly in functionality. It is uncertain whether all PGs studied would be able to perform acid- catalyzed esterification. Since there exists no single known reference-type reaction that could be performed with every PG, it is preferable to consider physical properties of a PG from theoretical models than empirically determined chemical properties from reactions.

The realization regarding physical properties as superior over chemical ones led Datta and Majumbar to propose the θR steric-bulk parameter for an alkyl group (R) as a cone angle19. Their method is more modern in the sense that it is devoid of electronic effects because it uses constructed Corey-Pauling-Koltun molecular models. By a strong correlation between θR and E’S, the Taft-Ingold hypothesis regarding acid-catalyzed hydrolysis of esters to be controlled solely by steric effects and not electronic effects is

19 reported to be valid . However, the θR cone angle is still not an adequate candidate for quantifying the steric bulk of PGs because it was found that the θR cone angles of CEt3,

C(i-Pr)3 and C(t-Bu)3 are not just conformation dependent, which is to be expected, but

severely conformation-limited19. That is, the cone angles of all three of those β-branching alkyl groups are indistinguishable in staggered conformation. It would seem that the problem could be remedied by choosing a different conformation. However, results state

11 that staggered PMe3 gives the same Tolman cone angle as the θR of staggered CMe3 .

Additionally, non-staggered phosphine analogs of the β-branching groups above provide varying Tolman cone angles. Finally, those phosphine analogs under the θR treatment provide indistinguishable cone angles. Therefore, the θR approach cannot account for changes in bulk due to β-branching on simple alkyl groups, let alone complex PGs.

A recent development in quantifying steric bulk is the free program SambVca that

20 provides a steric descriptor %VBur, the buried volume of a metal in its ligands . The application is used for organometallics, particularly with N-Heterocyclic Carbene (NHC)

20 ligands that are poorly described by the Tolman angle due to their C2-symmetric shapes .

Just like the approach proposed in this work, SambVca utilizes Cartesian coordinates to output a steric parameter. While this theoretical method is also promising, %VBur is a more suitable measure for the relative protection of a metal center than for the absolute size of a

PG. Instead of examining the size of the ligand itself, %VBur is perhaps more appropriate for examining the relationship of a ligand’s bulk to its metal. Indeed, its use has been reported for elucidating the properties of several metal complexes21-23.

Ligand repulsive energy ER, which also employs the method of first calculating energy-minimized structures, is comprehensive for many organometallics24. Theoretically,

ER could calculate steric bulk for organic PGs if the ligands were tailored to be PGs. The

Pd-PG method also uses a theoretical computation of an energy-minimized structure.

However, the ligand repulsive energies are limited by ligand/PG complexity. The ligand repulsive energies measure the steric bulk of various organic substituents, but only a few of them are commonly used organic PGs. Additionally, the ligand repulsive energy steric parameter is a measure of energy per mol (kcal mol-1), so direct comparison to cone angles

(deg.) calculated by the Pd-PG method requires further analysis.

Thus, there is a case to be made for why the exact cone angle and exact solid cone angle created by Bilbrey would facilitate the construction of a comprehensive series of PG steric bulk calculations. A series of exact cone angle and solid cone angle calculations for organic PGs is worthy for understanding the differences in size of organic PGs and optimizing organic and peptide syntheses3.

CHAPTER II

COMPUTATIONAL RESULTS

Section 2.1: Computational method

Optimized geometries of all molecules were computed using the B3LYP25 density functional by means of the Spartan ’16 package17. Since the molecules used palladium for the vertex atom of the cone angle, the LANL2DZ basis set was used for electronic structure computations26. For first-row and second-row atoms, the Pople basis set 6-31G* was employed27. Computed molecules were extracted as XMol files and ran through the

FindConeAngle and FindSolidAngle Mathematica packages, computing θo and Θo respectively14-15.

Figure 6: Schematic for obtaining the exact solid and exact cone angles of TMS.

The Mathematica packages themselves provided visualizations of the PG cone angles, as seen in Figures 4 and 5. XYZ format files were visualized on Mercury 3.8 for the pictures

provided in the Appendix28. Any singly-bonded organic PG can be accomodated using this method.

Some equilibrium-optimized Pd-PG molecules possessed an intramolecular attraction between the Pd vertex and a part of the PG that affected the exact cone and solid cone angles noticeably. Intramolecular interactions between Pd and PG are undesirable because the equilibrium-optimized Pd-PG is supposed to represent organic PGs in their native behavior. PGs in all-organic environments typically do not interact with their protected molecule like metals and organic substituents. Thus, a method for eliminating intramolecular attractions was created. In this work, only constraints through dihedral angle to retain conformation were used, though there could be other methods of retaining conformation, such as restraining interatomic distances. The PGs that experienced unwarranted intramolecular attractions, when optimized as-is, were o-nitrobenzyl, Psec,

Nps, o-nitrobenzyloxycarbonyl, phenacyl, PhFl, and 3-nitro-2-naphthylmethyl. Table 1 presents the constrained cone angle values for those PGs to be the accepted values.

To remedy the problem of unwanted intramolecular attractions, for this set of PGs the structure of each palladium-optimized PG was first energy-minimized with a methoxy group (-OMe) in place of the palladium to gain intuition about the natural conformation of the PG, as if it were present on an organic molecule. Then, the geometry of the natural conformation was retained by applying constraints to the dihedral angle between the methoxy replacement and the protecting group. Then, with constraints in place, the palladium was substituted back in place of the methoxy group and the molecule was recomputed using the palladium as a vertex atom to install the standard Pd-PG bond length.

For molecules that did not undergo intramolecular attraction upon equilibrium solving, the palladium version of the molecule was assumed to not differ from the all-organic environment, since the purpose of palladium in all calculations is to act as a standardized vertex atom.

Section 2.2: Computed cone angles

Due to the assumption of rotational freedom when calculating exact cone angle and rotational hindrance when calculating solid cone angle, a PG’s exact cone angle should always be greater than its exact solid cone angle for this method to remain sound. This requirement is intuitively evident for the approach to remain valid because the exact cone angle is a representation of the PG in its rotationally-free state while the exact solid cone angle represents a rotationally frozen state.

Bilbrey’s discussion engages ligand environments around metal centers. In that

o o o context, it is sensible to provide a range of θ cone angles (θ min , θ max) parameters for an array of Pd, Ni, and Pt complexed monodentate phosphine and amine ligands14. Metal complexes, as additional substituents are added to crowded metal centers, force ligands into minimum conformations14. This is unlikely to be the case for the majority of organic

PGs, as they are centered around oxygens and nitrogens that do not accompany more than one substituent. The only comparable effect for forcing minimum conformations of organic substituents on PGs would be due to β-branching, but entire PGs do not undergo minimum conformations due to other PGs bonded to the same protected atom. Thus, we are satisfied with proposing a single, equilibrium-optimized conformation for calculation of organic PG

steric bulk. It is possible for organic PG conformations to behave differently than their equilibrium conformation due to extrinsic factors, but it is complicated to account for these extrinsic factors. Rather, a single, standardized steric descriptor that intrinsically describes the steric bulk of PGs is needed.

The Pd-PG method does not tell which PGs are more rigid, so it is not inherently implied whether the exact cone angle or solid cone angle better represents the default state.

Rather, it is up to the intuition of the user to assess the behavior of the PG in question.

Furthermore, the user must consider the environment of the organic PG and intramolecular interactions between protected molecule and PG. One might argue that the closer the values of θo and Θo are, the more the PG behaves rotationally unhindered and the exact cone angle approximation should be assumed, and vice-versa. However, this assumption is not supported, and if it seems that it is supported, it is only because rigidity is loosely related to asymmetry. That is, asymmetric PGs are not always rigid (e.g. TBDMS), but PGs that are rigid rarely provide uniformly symmetrical steric hindrance to the protected molecule.

In any case, PG rotation allows for a symmetrical distribution of bulk in the shape of a cone.

Table 1. Exact cone angles (θo) and exact solid cone angles (Θo) for 60 hydroxyl (O) and amine (N) protecting groups. a Protecting group is photoremovable29.

o o Protecting Group (abbrev.) θ , deg Θ , deg Type

acetyl (Ac) 126.8 120.8 O allyl 126.7 118.6 O allyloxycarbonyl (Alloc) 146.0 130.2 O,N benzoyl (Bz) 154.3 129.2 O benzyl (Bn) 127.2 121.1 O,N benzylocarbonyl (Cbz) 147.4 130.1 N benzyloxymethyl (BOM) 141.6 121.8 O,N tert-butoxycarbonyl (BOC) 168.6 145.6 N tert-butyl 137.4 128.6 O tert-butyldimethylsilyl (TBDMS) 148.8 134.7 O,N tert-butyldiphenylsilyl (TBDPS) 185.6 152.3 O,N chloroacetyl (AcCl) 125.7 120.7 O chlorodimethylsilyl 132.0 128.5 O 2,7-dibromo-9-phenyl-9-xanthenyl 176.7 154.0 O diethylisopropylsilyl (DEIPS) 172.5 145.1 O 3,4-dimethoxybenzyl (DMB) 132.7 122.8 O diphenylmethyl 157.1 135.7 N 2-ethoxyethyl (EE) 153.0 126.9 O 9-fluorenylmethoxycarbonyl (Fmoc) 150.2 130.7 N p-hydroxyphenacyla 131.6 122.8 O p-methoxybenzyl (PMB) 132.9 122.7 O,N methoxycarbonyl 145.7 129.6 N 2-methoxyethoxymethyl (MEM) 145.9 122.7 O methoxymethyl (MOM) 121.2 116.0 O,N 1-methoxy-1-methylethyl (MME) 156.1 131.8 O p-methoxyphenyl (PMP) 135.6 120.6 N methyl (Me) 113.3 113.3 O methylthiomethyl (MTM) 143.3 124.8 O 2-napthylmethyl (NAP) 163.2 131.6 O o-nitrobenzyla 154.0 125.8 O,N p-nitrobenzyl (PNB) 133.2 125.1 O (carboxyl) o-nitrobenzyloxycarbonyla 145.1 125.4 O,N p-nitrocinnamyloxycarbonyl (Noc) 144.5 129.4 N o-nitrophenylsulfenyl (Nps) 154.5 126.9 N 3-nitro-2-naphthylmethyl (NNM)a 174.3 143.3 O,N phenacyla 163.1 135.1 O,N 9-phenyl-9-fluorenyl (PhFl) 170.7 145.9 N

Table 1 cont.

o o Protecting Group (abbrev.) θ , deg Θ , deg Type

phenylsulfonyl 118.3 110.6 N 2-phenylsulfonylethylcarbonyl (Psec) 190.0 156.7 N 9-phenyl-9-xanthenyl (pixyl) 176.3 152.3 O pivaloyl (Pv) 153.7 134.0 O isopropyldimethylsilyl (IPDMS) 148.1 129.6 O tetrahydropyran-2-yl (THP) 125.4 119.1 O thexyldimethylsilyl (TDS) 151.9 139.1 O triisopropylsilyloxycarbonyl (Tsoc) 186.8 162.6 N 2,2,2-trichloroethoxycarbonyl (Troc) 142.9 128.8 N triethylsilyl (TES) 171.5 140.1 O trifluoroacetyl 141.4 126.2 N tri-n-hexylsilyl 172.4 143.1 O triisopropylsilyl (TIPS) 177.9 145.2 O,N triisopropylsilyloxymethyl (TOM) 166.7 134.1 O trimethylsilyl (TMS) 124.6 124.5 O,N 2-(trimethylsilyl)ethanesulfonyl (SES) 119.8 107.2 N 2-(trimethylsilyl)ethoxycarbonyl (Teoc) 145.2 131.1 N 2-(trimethylsilyl)ethoxymethyl (SEM) 149.3 124.5 O,N 2-(trimethylsilyl)ethyl (TMSE) 178.7 141.2 O triphenylsilyl (TPS) 161.9 141.1 O 4-4'-4''-tris(benzoyloxy)trityl (TBTr) 209.9 165.2 O tosyl (Ts) 118.0 110.1 N trityl (Tr) 179.1 154.3 O,N

Section 2.3: Protecting group symmetry

As can be seen from Table 1, the exact cone angle was calculated to be equal to the corresponding exact solid cone angle for just two cases: Me and TMS. The result is not surprising because of the simplicity and symmetry of the substituents.

Surprisingly, the smallest Θo was not from methyl, but SES. We reason why the exact solid cone angle of SES is smaller than that of Me because the two double-bonds between sulfur and oxygen contain sp2 hybridized orbitals and only contribute the shadow of two oxygens total. On the other hand, Me contributes smaller shadows in the form of hydrogens but they are equally as proximate to the vertex atom and there are three hydrogens total.

The –SO2– group far removes the ring bulk from the vertex atom because of the long sulfur single bonds in Pd–S–R, as the ring portion of SES does not seem to contribute much to the total shadow. This is the first time a steric descriptor for any –SO2– derivative PG has been calculated, but we reason that this PG family is not sterically bulky.

The phenomena of differing exact and solid cone angles in asymmetric PGs is exhibited, for example, in TBDMS. The individual methyl substituents of the asymmetrical silyl PGs do not contribute as much shadow to the solid cone angle calculation as the tert- butyl group. However, the bulky tert-butyl group, when rotated, traces the maximum amount of cone angle by itself, without requiring the smaller substituents to contribute.

Thus, the difference between solid and exact cone angles is more likely an indicator of the asymmetry of the PG, and not an indicator of the PG’s rigidity.

Section 2.4: Silyl protecting groups

Silyl PGs for alcohols possess more functions than only protection through electronic properties. The TIPS PG has been reportedly used as a regio- and stereodirecting group9.

As regiodirectors, silyl PGs protect the atom to which they are attached as well as nearby atoms. The bulkiest silyl groups, such as TIPS, have been shown to exhibit even γ-directing effects9-10. Silyl groups sterically smaller than TIPS provide almost no γ-products, but no quantitative threshold of steric bulk is known because no steric descriptors for organic PGs have ever been calculated.

Table 2. Silyl PG exact cone angles and exact solid cone angles, with analogous Tolman angle approximations9,11.

o o Silyl PG (abbrev.) θ, deg θ , deg Θ , deg

trimethylsilyl (TMS) 118 124.6 124.5 triethylsilyl (TES) 132 171.5 140.1 tri-n-hexylsilyl 136 172.4 143.1 isopropyldimethylsilyl (IPDMS) - 148.1 129.6 tert-butyldimethylsilyl (TBDMS) 139 148.8 134.7 thexyldimethylsilyl (TDS) - 151.9 139.1 triisopropylsilyl (TIPS) 160 177.9 145.2 chlorodimethylsilyl 120 132.0 128.5 triphenylsilyl (TPS) 145 161.9 141.1 diethylisopropylsilyl (DEIPS) - 172.5 145.1

Ruecker notes that TMS and TBDMS allyl ethers in the allyl anion α/γ problem do not prevent reaction of the α-position resonance contributor. The allyl anion α/γ problem is summarized in Figure 7 as follows:

Figure 7: The allyl anion α/γ problem. (a) nBuLi/TMEDA. (b) R’ R’’CO. PG = TIPS ; PG

≠ TMS, TBDMS.

Ruecker reports that the TIPS-OTf electrophile increase γ-selectivity even more. The

Tolman angle of TBDMS and TIPS only differ by 21o, which is a sizeable amount, but not necessarily sufficient to explain the increase in γ-selectivity. The results in Table 2 clarify

Ruecker’s observation, as the exact cone angle of the TIPS PG is seen to be 17.9o greater than its analogous Tolman angle while the exact cone angles of TMS and TBDMS only show an increase by 6.6o and 9.8o, respectively. This indicates that the TIPS PG exists in an equilibrium conformation that creates larger steric bulk than previously approximated.

Furthermore, it is evidence that the allyl anion α/γ phenomenon is due to steric effects. The

TBDMS and TIPS PGs exhibit a greater disparity in exact cone angle of 29.1o, as opposed to the 21o difference previously approximated. The α/γ allyl anion phenomena, while feasibly supported by Tolman angle calculations alone, is further explained and supported using equilibrium-optimized theoretical models of silyl PGs.

Another phenomena in the silyl PGs is that increasing the n-alkyl chain length of silyl

PG substituents to chains longer than ethyl provides meager returns in steric bulk, while introducing β-branching noticeably increases steric bulk. The exact cone angle of TES is only 0.9o less than that of tri-n-hexylsilyl. In turn, the exact cone angle of TMS is 46.9o

smaller than TES. This gives insight into the equilibrium conformations of the ethyl groups on silyl PGs, in that they are particularly effective at increasing exact cone angle in an equilibrium-optimized conformation.

Figure 8: Visualization of equilibrium-optimized TPS xyz coordinates using Mercury

3.828.

The opposite could be argued for phenyl rings; when going from Tolman angle approximations to the Pd-PG method, TPS has a noticeably smaller increase in exact cone angle over TMS than TIPS and TBDMS despite the intuition that rings provide significant bulk increases over methyl substituents. Therefore, aromatic rings are not as bulky as intuitively thought, but can unlock unique ring-packing conformations due to crowding; in

TPS, two of the phenyl rings are almost vertical while the remaining ring is laid flat (Figure

8). The vertical rings push the outermost atom of the cone close to the vertex, thus increasing the exact cone angle. This is evident in the significant increase of exact cone angle rather than exact solid cone angle over TMS when switching to the Pd-PG approach from Tolman angles. Additionally, this equilibrium conformation is unique to TPS. In close

proximity to the Si center, phenyl rings appear to be doubly β-branched substituents.

However, TIPS does not undergo this unique substituent packing in equilibrium optimization, despite being doubly β-branched.

A systematic study of steric influence by protecting groups on organic synthetic yield is observed in the Mitsunobu reaction30. The desired adduct of N-hydroxyphthalimide to a secondary alcohol substrate with varying hydroxyl PGs neighboring the adduction site is seen in Figure 9, with one of the PGs studied being the TIPS group.

Figure 9: Desired Mistunobu reaction adduct from a systematic study of protecting group steric influence30.

The steric bulk of each PG, most evidently in the exact cone angle, was found to be inversely proportional to the yield of the reaction as follows: PG = MOM (θo = 121.2o, Θo

= 132.9o, 92% yield), PMB (θo = 132.9o, Θo = 122.7o, 93% yield), SEM (θo = 149.3o, Θo =

124.5o, 67% yield), TBS (θo = 148.8o, Θo = 134.7o, 66% yield), TIPS (θo = 177.9o, Θo =

145.2o, 35% yield). The exact cone angle models the inverse relationship better than the

exact solid cone angle because the singly-bonded protected alcohol (–O–PG) is rotationally unhindered. The TIPS group is again seen to exert the greatest steric influence by mediating the yield of the Mitsunobu reaction, though in a manner opposite of the intended effect.

Thus, an example of synthetic optimization with PGs of similar electronics but different steric influence is observed. For the steric descriptors proposed in this work, empirical evidence is currently the only way of knowing their accuracy due to the nonexistence of

PG steric descriptors in literature, particularly for complex PGs like PMB and SEM.

Section 2.5: Constraints for conformations caused by intramolecular attractions

Intramolecular attractions of equilibrium-optimized theoretical molecular models introduce conformations that PGs would not undergo in their native, organic environment, resulting in a violation of modelling native PG behavior and therefore criteria (ii). In this work, an “organic environment” refers to the environment that an organic PG would experience from the organic molecule being protected, and not from the chemical medium.

Since both protected molecule and PG tend to be composed of functionalized hydrocarbon, the intramolecular interactions between most organic molecule and PG should be considered nonexistent, or null. We define the equilibrium-optimized conformation of an organic PG with a methoxy in place of the palladium as the “null conformation” because there are no non-native interactions.

Table 3. Comparison of protecting groups undergoing intramolecular interactions before and after applying dihedral constraints. The ‘c’ subscript indicates the use of dihedral constraints.

o o o o o o Protecting Group (abbrev.) θ θ c Δθ Θ Θ c ΔΘ

o-nitrobenzyl 174.5 154.0 -20.5 143.3 125.8 -17.5 o-nitrobenzyloxycarbonyl 142.0 145.1 3.1 124.4 125.4 1.0 o-nitrophenylsulfenyl (Nps) 174.9 154.5 -20.4 136.6 126.9 -9.7 3-nitro-2-naphthylmethyl (NNM) 174.3 153.3 -21.0 143.3 125.4 -17.9 phenacyl 140.8 163.1 22.3 127.0 135.1 8.1 9-phenyl-9-fluorenyl (PhFl) 168.6 170.7 2.1 148.4 145.9 -2.5 2-phenylsulfonylethylcarbonyl (Psec) 208.7 190.0 -18.7 166.7 156.7 -10.0

The most common non-native interaction found in the set of PGs in Table 3 is Pd coupling to a nitro group on aromatic rings. The method for selectively removing conformations induced by intramolecular attractions can be visualized:

Figure 10: Examples of equilibrium-optimized 3-nitro-2-naphthylmethyl. (a) 3-nitro-2- naphthylmethyl, “as-is” non-null equilibrium-optimization with palladium; (b) the null conformation of 3-nitro-2-naphthylmethyl; (c) equilibrium-optimized Pd-PG in null conformation with dihedral constraints taken from (b) about the methyl-naphthyl bond.

It is reasonable to see that the conformations in Figures 10a and 10c would yield different cone angles; indeed, the null conformation calculations for the Pd-PG method reduced the exact cone angle and exact solid cone angle of 3-nitro-2-naphthylmethyl by 21.0o and 17.9o degrees, respectively. Intuitively, the reduction in cone angle is consistent with the distancing of the nitro group from the Pd vertex. Thus, for PGs exhibiting intramolecular attractions, preliminary cone angle results calculated as-is (Figure 10a) should be replaced with dihedral-constraint calculated values from the null conformation approach (Figure

10c). Table 1 already displays results from computations with constraints when needed and does not include non-null conformation calculations. In general, most PGs did not require constraints to fulfill native behavior criteria (ii).

CHAPTER IV

CONCLUSIONS

In this thesis, the steric descriptors of exact cone angle (θo) and exact solid cone angle

(Θo) are calculated for 60 organic PGs and discussed in comparison to other literature methods. Based on this approach, this is the first time there are calculated exact cone angles and solid cone angles for multiple families of organic PGs. The steric bulk of organic PGs is not limited in this approach by functionality, size, or complexity. Many more organic

PGs can be calculated using this method with ease, as there is no kinetic data or crystallization requirements. The molecules used for computations were generated using the B3LYP basis set, accompanying any functionality on the PG, including alkane, organosilane, alkyl halide, and nitro-substituted aromatic, though the list is not exhaustive.

The steric bulk of asymmetrical and complex PGs is also computable by this method, unlike for previous literature methods.

The hypothesis that the exact cone angle should always be greater than or equal to its corresponding exact solid cone angle is observed to be true. We observe that in our approach, asymmetrical PGs tended to obtain a larger disparity in exact cone angle and solid cone angle.

The results obtained from our method were different from the Tolman angle but exhibited correlation. That is, the family of silyl PGs maintained the same hierarchy of steric bulk as from the Tolman angle approximation. Exact cone angles tended to be larger

than analogous Tolman angle approximations because the Pd-PG method can better account for energy-minimized conformations, as seen in the difference in exact cone angle between TMS and TPS.

For equilibrium-computed molecules undergoing interactions between the metal and the PG that would not occur in the native environment of an organic PG were reconcilable by using dihedral constraints. Thus, the Pd-PG approximation is a robust method for calculating the exact cone angle and exact solid cone angle of organic PGs.

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APPENDIX

XYZ files of all equilibrium-solved Pd-PG with associated pictures

Pd – blue C – dark grey H – light grey O – red Si – light yellow Cl – green Br – orange S – dark yellow N – purple F – light green acetyl (Ac)

Pd -0.760923 0.478160 2.192494 C -0.742727 -0.071064 0.303146 O -1.799579 -0.455614 -0.192616 C 0.578753 0.004899 -0.445722 H 1.085564 0.950176 -0.234212 H 0.408452 -0.100044 -1.522959 H 1.230461 -0.806513 -0.100131

Allyl

Pd -0.467879 0.994432 2.177984 C 0.735820 0.644987 0.538518 H 1.734201 0.490482 0.958180 H 0.679657 1.547578 -0.078351 C 0.097905 -0.541868 -0.024270 H 0.376394 -1.497743 0.420738 C -0.802698 -0.546000 -1.044703 H -1.256083 -1.464580 -1.402510 H -1.097317 0.372713 -1.545588 allyloxycarbonyl (Alloc)

Pd -0.124118 -0.000740 3.411883 C 1.184162 0.000114 1.914378 O 2.373675 0.000348 2.220588

O 0.790128 0.000253 0.594866 C -0.644199 0.000171 0.273763 H -1.106467 -0.888454 0.725328 H -1.106526 0.888726 0.725397 C -0.820324 0.000102 -1.215197 H -1.863423 0.000202 -1.530827 C 0.163881 -0.000165 -2.117781 H -0.053138 -0.000254 -3.181253 H 1.206348 -0.000303 -1.821146 benzoyl (Bz)

Pd -0.258054 -0.000072 -3.721843 C 0.923666 0.000010 -2.136504 O 2.137762 0.000042 -2.375119 C 0.350347 0.000011 -0.762477 C -0.692645 -0.000005 1.838663 C 1.218585 -0.000000 0.347843 C -1.039173 0.000016 -0.557708 C -1.559593 0.000008 0.738605 C 0.695864 -0.000009 1.641448 H 2.289336 -0.000004 0.174387 H -1.700762 0.000025 -1.420917 H -2.633951 0.000011 0.891262 H 1.365052 -0.000019 2.495979 H -1.096435 -0.000012 2.846380

benzyl (Bn)

Pd 2.829335 0.096725 1.841664 C 1.697414 -1.197249 0.707551 H 1.439429 -1.998418 1.407986 H 2.374211 -1.553328 -0.075963 C 0.542427 -0.428304 0.211154 C -1.683772 1.036265 -0.752903 C 0.568317 0.189661 -1.063443 C -0.635833 -0.291203 0.986951 C -1.729854 0.432157 0.511874 C -0.528863 0.909018 -1.537513 H 1.457674 0.087740 -1.679007 H -0.680074 -0.763267 1.964694 H -2.623003 0.521505 1.122891 H -0.488987 1.366050 -2.521707 H -2.538420 1.592646 -1.124230

benzylocarbonyl (Cbz)

Pd -0.729393 3.725321 2.623706 C 0.345941 3.391274 0.986832 O 0.879177 4.374437 0.477907 O 0.505965 2.135678 0.442827 C -0.154084 0.979854 1.086480 H 0.340590 0.777174 2.041557 H -1.198176 1.259036 1.285337 C -0.056975 -0.204691 0.163124 C 0.031494 -2.457628 -1.515046 C -0.274558 -0.068134 -1.217577 C 0.211222 -1.475962 0.693000 C 0.248495 -2.599216 -0.140326 C -0.224747 -1.188960 -2.051152 H -0.458546 0.916040 -1.633869 H 0.394219 -1.587911 1.758485 H 0.456029 -3.577406 0.281723 H -0.384119 -1.072486 -3.118449 H 0.067466 -3.326422 -2.164559

benzyloxymethyl (BOM)

Pd -3.936907 0.190125 2.136009 C -3.295149 0.776886 0.296607 H -3.225598 1.875114 0.304589 H -4.027314 0.406164 -0.424441 O -2.048226 0.158353 -0.013579 C -0.874401 0.744838 0.629240 H -0.868517 1.826263 0.414735 H -0.955426 0.620007 1.717646 C 0.372660 0.078798 0.104529 C 2.743115 -1.080087 -0.870783 C 0.453396 -0.356788 -1.227361 C 1.487170 -0.076342 0.943118 C 2.668676 -0.647527 0.457917 C 1.631057 -0.936696 -1.709610 H -0.414173 -0.255683 -1.869111 H 1.429486 0.246156 1.979620 H 3.523139 -0.762678 1.117645 H 1.680392 -1.277318 -2.739348 H 3.656619 -1.529586 -1.247421

tert-butoxycarbonyl (BOC)

Pd 0.213774 0.001641 3.078583 C 1.599735 0.000635 1.650751 O 2.759793 0.000841 2.067409 O 1.349947 -0.000522 0.300089 C -0.031694 -0.000271 -0.304545 C -0.765023 -1.278936 0.114261 H -0.181379 -2.162242 -0.162069 H -1.740303 -1.333276 -0.382687 H -0.932078 -1.302558 1.199778 C 0.279216 -0.000043 -1.805074 H 0.859586 -0.887156 -2.073559 H 0.859604 0.887125 -2.073345 H -0.652986 0.000028 -2.380831 C -0.764908 1.278350 0.114672 H -0.932751 1.301237 1.200078 H -1.739782 1.333470 -0.382985 H -0.180751 2.161679 -0.160527

tert-butyl

Pd 0.000530 0.000000 2.375521 C -0.000006 -0.000000 0.310108 C 0.734125 1.270919 -0.127843 H 1.768308 1.288682 0.234202 H 0.227230 2.175593 0.225922 H 0.770781 1.325061 -1.231386 C -1.468336 0.000000 -0.125727 H -1.998925 -0.888997 0.233691 H -1.535225 0.000002 -1.229078 H -1.998926 0.888996 0.233693 C 0.734125 -1.270919 -0.127843 H 0.227230 -2.175594 0.225923 H 1.768308 -1.288682 0.234203 H 0.770781 -1.325062 -1.231386

tert-butyldimethylsilyl (TBDMS)

Pd -0.187173 0.000117 3.164545 Si 0.665241 -0.000018 0.952729 C 1.765443 -1.544444 0.706128 H 1.206658 -2.474139 0.854327 H 2.599057 -1.539577 1.417476 H 2.191075 -1.559543 -0.306911 C -0.797674 -0.000004 -0.337009 C 1.765452 1.544425 0.706118 H 2.191073 1.559531 -0.306923 H 2.599066 1.539545 1.417466 H 1.206658 2.474113 0.854337 C -0.212119 0.000015 -1.772815 H 0.403640 -0.887723 -1.961512 H 0.403626 0.887766 -1.961493 H -1.028820 0.000017 -2.510460 C -1.673929 1.260792 -0.146732 H -2.496767 1.264312 -0.877058 H -1.098032 2.182935 -0.291176 H -2.116902 1.292886 0.857015 C -1.673918 -1.260811 -0.146753 H -1.098016 -2.182946 -0.291228 H -2.496764 -1.264319 -0.877070 H -2.116876 -1.292931 0.857000

tert-butyldiphenylsilyl (TBDPS)

Pd 0.004893 -0.000002 3.205223 Si -0.108926 0.000003 0.824841 C -1.987051 0.000003 0.275274 C -2.080423 0.000011 -1.271548 H -1.611234 -0.889959 -1.706809 H -1.611196 0.889963 -1.706806 H -3.137402 0.000029 -1.577123 C -2.686249 -1.263725 0.826337 H -2.201966 -2.180604 0.470733 H -3.736431 -1.286977 0.499259 H -2.676954 -1.278759 1.923954 C -2.686253 1.263724 0.826348 H -2.201972 2.180607 0.470754 H -2.676963 1.278745 1.923965 H -3.736434 1.286976 0.499267 C 0.763986 -1.591198 0.216396 C 2.033458 -4.004339 -0.577764 C 1.130980 -1.819224 -1.128062 C 1.052342 -2.613349 1.146200 C 1.678542 -3.803961 0.760498 C 1.756685 -3.008422 -1.521102 H 0.930829 -1.068275 -1.885304 H 0.782883 -2.468367 2.190994 H 1.888558 -4.569636 1.501411 H 2.028234 -3.155568 -2.562340 H 2.520689 -4.925342 -0.882848 C 0.764000 1.591193 0.216404 C 2.033468 4.004342 -0.577758 C 1.052279 2.613380 1.146191 C 1.131085 1.819181 -1.128033 C 1.756779 3.008386 -1.521077

C 1.678479 3.803995 0.760489 H 0.782765 2.468425 2.190974 H 0.931020 1.068197 -1.885260 H 2.028384 3.155505 -2.562304 H 1.888439 4.569695 1.501392 H 2.520695 4.925346 -0.882842 chloroacetyl (AcCl)

Pd 0.563105 0.690203 2.281174 C -0.021246 0.760461 0.392618 O -0.344078 1.847519 -0.066209 C -0.004998 -0.571896 -0.311815 H 0.985279 -1.024709 -0.261250 H -0.748206 -1.240616 0.125134 Cl -0.429856 -0.460962 -2.159653

chlorodimethylsilyl

Pd 0.038411 -0.000571 -2.879329 Si 0.308530 0.000098 -0.557804 C -0.270289 1.566931 0.339371 H -1.363867 1.640395 0.302640 H 0.148970 2.464128 -0.124296 H 0.040843 1.544485 1.390829 C -0.270308 -1.566813 0.339277 H -1.363885 -1.640285 0.302473 H 0.040779 -1.544509 1.390748 H 0.148968 -2.463948 -0.124503 Cl 2.541849 0.000090 -0.379405

2,7-dibromo-9-phenyl-9-xanthenyl

Pd -2.554399 0.000444 0.770614 C -0.548137 0.000337 0.096921 C -0.413634 0.000057 -1.412669 C -0.070810 -0.000514 -4.215927 C 0.875803 -0.000234 -1.983204 C -1.523539 0.000067 -2.273226 C -1.355306 -0.000220 -3.663855 C 1.045914 -0.000518 -3.370116 H 1.745084 -0.000250 -1.332232 H -2.523171 0.000303 -1.844551 H -2.226963 -0.000214 -4.310559 H 2.047134 -0.000743 -3.789352 H 0.060516 -0.000737 -5.293206 C -0.149135 1.249402 0.797288 C 0.542212 3.607681 2.232466 C 0.293796 1.208778 2.141117 C -0.202027 2.521906 0.176161 C 0.130577 3.660314 0.896978 C 0.630218 2.358593 2.851795 H -0.509971 2.592438 -0.858979 H 0.962922 2.260694 3.878087 H 0.797158 4.510154 2.772262 C -0.149743 -1.248674 0.797738 C 0.540442 -3.606775 2.233786 C 0.293208 -1.207778 2.141563 C -0.203227 -2.521386 0.177064 C 0.128808 -3.659692 0.898304

C 0.629055 -2.357502 2.852662 H -0.511170 -2.592145 -0.858062 H 0.961796 -2.259393 3.878921 H 0.794931 -4.509180 2.773914 O 0.423902 0.000595 2.830637 Br 0.016716 -5.431905 0.005934 Br 0.019322 5.432257 0.003964 diethyl-iso-propylsilyl (DEIPS)

Pd -2.601344 -0.001448 -0.286842 Si -0.228213 -0.001214 -0.073535 C 0.490696 -1.588338 -0.896923 H 0.279104 -2.433591 -0.228579 H 1.587669 -1.481419 -0.914290 C -0.021158 -1.926927 -2.311614 H 0.407868 -2.870135 -2.673965 H 0.238036 -1.149401 -3.038863 H -1.113347 -2.033593 -2.319865 C 0.491206 1.583574 -0.901210 H 1.587161 1.469837 -0.931681 H 0.292689 2.428546 -0.228519 C -0.034751 1.929083 -2.309137 H 0.208009 1.150068 -3.040430 H 0.398766 2.868709 -2.675476 H -1.125880 2.046291 -2.303775 C 0.265309 0.000111 1.801439 H 1.369993 -0.001194 1.812804 C -0.214383 1.268055 2.541050 H 0.119314 1.256522 3.587879 H -1.311349 1.325922 2.544706 H 0.167602 2.187102 2.082576 C -0.217359 -1.265717 2.542780 H 0.161588 -2.186275 2.084827

H -1.314486 -1.320385 2.547327 H 0.117261 -1.254181 3.589315

3,4-dimethoxybenzyl (DMB)

Pd -3.009532 0.049256 3.457325 C -3.251787 -0.135362 1.418935 H -3.815206 0.755800 1.124850 H -3.841134 -1.047167 1.279103 C -1.882992 -0.201997 0.880877 C 0.765845 -0.317153 -0.138143 C -1.170926 0.975684 0.541326 C -1.228648 -1.438089 0.675832 C 0.073301 -1.494241 0.174822 C 0.125778 0.931966 0.044644 H -1.627170 1.950565 0.674726 H -1.750166 -2.360925 0.910659 H 0.544460 -2.459454 0.033187 O 2.069014 -0.282019 -0.624208 O 0.773925 2.147342 -0.181620 C 2.794260 -1.532119 -0.765492 H 3.784766 -1.247777 -1.118615 H 2.313736 -2.190487 -1.498696 H 2.877515 -2.049834 0.196677 C 1.273804 2.420410 -1.532796 H 2.070906 1.725675 -1.801626 H 1.653626 3.441473 -1.490169 H 0.456628 2.358450 -2.261599

diphenylmethyl

Pd -1.097242 -1.652181 1.979705 C -0.539777 -1.017148 0.069425 H -0.928006 -1.833857 -0.550483 C 0.947188 -1.017070 0.080847 C 3.782657 -1.181892 0.073576 C 1.747673 0.148265 0.047185 C 1.616292 -2.268923 0.078457 C 3.007363 -2.350557 0.081069 C 3.142672 0.062611 0.048029 H 1.278828 1.122560 -0.010589 H 1.021223 -3.178395 0.079325 H 3.489280 -3.323511 0.082960 H 3.732237 0.974138 0.017192 H 4.866229 -1.242329 0.074020 C -1.368255 0.208438 -0.060430 C -3.076047 2.463886 -0.302462 C -1.157816 1.377002 0.716625 C -2.467631 0.208000 -0.952903 C -3.306335 1.316626 -1.072961 C -1.999013 2.484827 0.593322 H -0.350151 1.399200 1.440341 H -2.653470 -0.677194 -1.554719 H -4.140283 1.287569 -1.767735 H -1.819015 3.363823 1.204862 H -3.728600 3.326111 -0.394658

2-ethoxyethyl (EE)

Pd 0.128707 1.453266 2.320228 C 0.297944 1.233977 0.294244 H 1.384272 1.220585 0.105925 C -0.425882 2.354991 -0.427137 H -0.019646 3.328392 -0.134546 H -1.496587 2.337774 -0.201592 H -0.312149 2.245289 -1.516324 O -0.298440 -0.011762 -0.069169 C 0.492888 -1.215796 0.190320 H 1.446926 -1.138736 -0.352102 H 0.712057 -1.278054 1.265103 C -0.322747 -2.407444 -0.280393 H 0.229314 -3.338963 -0.111206 H -0.546539 -2.323325 -1.348370 H -1.270118 -2.460193 0.265019

9-fluorenylmethoxycarbonyl (Fmoc)

Pd 0.015371 4.734035 2.048049 C 0.543041 4.258863 0.192943

O 0.638088 5.202416 -0.590203 O 0.799337 2.972046 -0.222197 C 0.660691 1.843696 0.718439 H 1.409990 1.954458 1.508715 H -0.341667 1.855822 1.157516 C 0.896527 0.564537 -0.091477 H 1.856523 0.682405 -0.615032 C -0.217140 0.233211 -1.082253 C -2.286008 -0.800137 -2.645110 C -0.700500 0.986462 -2.150765 C -0.764681 -1.039917 -0.792057 C -1.799922 -1.560829 -1.574118 C -1.742869 0.460834 -2.930881 H -0.281811 1.961539 -2.371606 H -2.223806 -2.537164 -1.359825 H -2.130238 1.036930 -3.765145 H -3.090010 -1.191508 -3.260591 C 0.916638 -0.674750 0.802077 C 0.599841 -3.103435 2.139737 C -0.064150 -1.601088 0.374218 C 1.736214 -0.963307 1.890722 C 1.571848 -2.185748 2.561921 C -0.223527 -2.818817 1.042454 H 2.500603 -0.263893 2.218548 H 2.205483 -2.423400 3.410455 H -0.970596 -3.537307 0.719211 H 0.486732 -4.045952 2.666256 p-hydroxyphenacyl

Pd -1.364082 3.681483 -0.735840 C 0.441158 2.724204 -1.038215 H 0.995480 2.789745 -0.099732 H 0.898203 3.321190 -1.832389 C 0.115176 1.361337 -1.516144 C 0.019979 0.224769 -0.550670 C -0.135520 -2.001289 1.156831 C -0.103056 -1.080371 -1.071306 C 0.054998 0.388184 0.845732 C -0.026586 -0.714159 1.698758 C -0.174625 -2.185840 -0.232683 H -0.134920 -1.195859 -2.148488 H 0.133152 1.378871 1.279196 H -0.004453 -0.572935 2.776235 H -0.257998 -3.193153 -0.622858 O -0.077649 1.151711 -2.746142 O -0.211440 -3.142703 1.942261 H -0.167817 -2.935186 2.895457 p-methoxybenzyl (PMB)

Pd 0.070880 0.000921 4.314721 C 0.192392 0.000127 2.326120 C 0.352306 -0.000446 -0.479849 C 1.445703 -0.000002 1.683698 C -0.973457 -0.000169 1.548647 C -0.900686 -0.000594 0.145370 C 1.525471 -0.000239 0.289352 H 2.363968 0.000159 2.263304 H -1.952436 -0.000023 2.018690 H -1.816791 -0.000801 -0.433773 H 2.481387 -0.000206 -0.222286 O 0.541721 -0.000307 -1.861750

C -0.624452 0.000345 -2.723097 H -1.238007 -0.895095 -2.565497 H -0.230212 0.000489 -3.738896 H -1.237786 0.895843 -2.564753 methoxycarbonyl

Pd -0.754012 1.868287 1.142419 C -0.142102 1.197262 -0.625287 O -0.112415 2.020376 -1.536722 O 0.225023 -0.111900 -0.840369 C 0.196637 -1.061716 0.276330 H 0.955658 -0.801229 1.018922 H 0.425737 -2.026304 -0.173537 H -0.794527 -1.084776 0.738245

2-methoxyethoxymethyl (MEM)

Pd 0.019486 3.487187 1.256273 C 0.027926 2.780395 -0.652416 H 1.072952 2.789458 -0.997023 H -0.612264 3.449594 -1.232298 O -0.550570 1.480431 -0.722394 C 0.287834 0.373293 -0.280457 H 1.268446 0.419208 -0.772923 H 0.439153 0.439492 0.805272

C -0.442640 -0.907353 -0.669758 H -0.528452 -0.972765 -1.756541 H -1.453595 -0.909168 -0.238750 O 0.306876 -2.080427 -0.254042 C 0.077895 -2.493710 1.118632 H 0.650049 -3.412781 1.253496 H -0.987311 -2.697247 1.298465 H 0.424215 -1.745610 1.844466 methoxymethyl (MOM)

Pd -0.226863 -0.002298 -2.928583 H -1.441127 0.000862 1.695002 C -0.460970 -0.000296 1.216929 H 0.100709 0.893913 1.521735 H 0.097892 -0.896696 1.520446 O -0.707080 0.000970 -0.220049 C 0.478237 0.000936 -1.033438 H 1.079160 0.911941 -0.886598 H 1.080042 -0.909332 -0.885445

1-methoxy-1-methylethyl (MME)

Pd -0.459927 0.484454 2.267563 C -0.303094 0.351334 0.221395 C -1.024936 -0.911540 -0.248995 H -0.650310 -1.818047 0.234605 H -0.906920 -1.028239 -1.339455 H -2.093908 -0.832472 -0.030550 C -0.871252 1.639151 -0.362703 H -0.295214 2.504353 -0.023690 H -1.918467 1.770744 -0.073798 H -0.817035 1.608237 -1.462500 O 1.104098 0.369988 -0.085898 C 1.896077 -0.821314 0.179182 H 2.928627 -0.531625 -0.017895 H 1.617294 -1.648737 -0.482919 H 1.794965 -1.136286 1.225659

p-methoxyphenyl (PMP)

methyl (Me)

Pd -0.000100 0.000003 1.829600 C -0.000053 -0.000002 -0.205798 H -0.521123 -0.903083 -0.541188 H 1.042398 -0.000001 -0.541432 H -0.521123 0.903083 -0.541181 methylthiomethyl (MTM)

Pd 0.505195 -1.800926 -1.743155 C 0.193829 0.168429 -1.412409 H -0.874327 0.391747 -1.335321 H 0.667549 0.742602 -2.213396 S 1.076857 0.594971 0.182284 C -0.219469 0.047785 1.447348 H -1.137753 0.619617 1.302737 H 0.198045 0.256393 2.433069 H -0.409927 -1.020617 1.338844

2-napthylmethyl (NAP)

Pd 0.000000 0.000000 1.000000 C 0.000000 0.000000 -1.023000 H 1.033319 0.000000 -1.388334 H -0.516660 -0.894880 -1.388333 C -0.721721 1.250056 -1.533333 H -0.772011 0.558425 -3.574099 C -1.040920 1.370138 -2.888515 C -1.710496 3.417535 -1.113911 C -1.695872 2.513591 -3.362263 C -1.056853 2.274814 -0.645112 C -2.032107 3.541717 -2.471123 C -2.017484 2.637773 -4.719475 H -0.811206 2.180179 0.418804 H -2.955968 5.496882 -2.259286 H -1.967418 4.213690 -0.405854 C -2.671126 3.780493 -5.188273 H -1.760561 1.841618 -5.427531 H -2.924783 3.871177 -6.250653 C -3.006258 4.805251 -4.300052 H -3.514909 5.704082 -4.666922 C -2.687059 4.685168 -2.944870

o-nitrobenzyl

Pd -0.201090 -2.191865 2.992944 H 0.014323 -0.363794 -3.335061 C 0.000481 -0.350562 -2.251128 C -0.035391 -0.309019 0.609753 C -0.103189 -1.540971 -1.521713 C 0.086633 0.857763 -1.568214 C 0.068278 0.874911 -0.165764 C -0.119309 -1.508675 -0.126416 H -0.171362 -2.493474 -2.037125 H 0.170459 1.799453 -2.093507 H -0.200968 -2.437721 0.430864 N 0.166359 2.201929 0.455122 O 0.286659 3.209459 -0.304278 O 0.128235 2.299064 1.717256 C -0.052434 -0.342722 2.117888 H 0.863173 0.080904 2.548330 H -0.900856 0.215319 2.531049

p-nitrobenzyl (PNB)

Pd -0.115475 3.103552 1.827464 C 1.444316 2.113712 0.889747 H 2.182371 1.911363 1.670049 H 1.821313 2.802929 0.129725 C 0.725916 0.943074 0.380057 C -0.746300 -1.258498 -0.556275 C 0.113835 0.959756 -0.904880 C 0.589092 -0.237274 1.163716 C -0.141248 -1.325648 0.706579 C -0.616556 -0.124599 -1.370428 H 0.222521 1.841508 -1.528077 H 1.065083 -0.281257 2.138155 H -0.252966 -2.223924 1.299697 H -1.086926 -0.117549 -2.344905 N -1.520829 -2.391062 -1.035205 O -1.637773 -3.402184 -0.277789 O -2.046376 -2.313900 -2.187630

o-nitrobenzyloxycarbonyl

Pd 0.862704 4.698581 -0.450767 C -0.500290 3.418358 0.175721 O -1.684625 3.708088 0.351970 O 0.019752 2.153396 0.367067 C -0.970643 1.070842 0.678718 H -1.251052 1.162618 1.730439 H -1.846694 1.231740 0.051240 C -0.292450 -0.243236 0.422865 C 1.020656 -2.737924 0.086918 C 0.231819 -0.644353 -0.824093 C -0.128722 -1.136529 1.494028 C 0.505247 -2.372143 1.334619 C 0.891880 -1.865238 -0.993283 H -0.501688 -0.845796 2.470547 H 0.604768 -3.039612 2.183850 H 1.290463 -2.110296 -1.968827 H 1.520813 -3.690543 -0.045563 N 0.110377 0.194129 -2.023903 O 0.963645 0.031139 -2.943321 O -0.845961 1.016780 -2.098223

p-nitrocinnamyloxycarbonyl (Noc)

Pd -1.181221 5.979296 2.016356 C -0.872486 4.934733 0.354539 O -0.909091 5.570824 -0.695423 O -0.634308 3.574827 0.341888 C -0.584904 2.830787 1.604441 H 0.203501 3.256514 2.240775 H -1.542779 2.952289 2.129677 C -0.315915 1.387588 1.311286 H -0.260731 0.764747 2.202333 C -0.153114 0.871175 0.081242 H -0.220246 1.548962 -0.764833 C 0.110073 -0.536152 -0.249214 C 0.610283 -3.185324 -1.004644 C 0.246653 -0.891971 -1.609431 C 0.234257 -1.555902 0.722202 C 0.481915 -2.873170 0.353523 C 0.495883 -2.206559 -1.994521 H 0.155199 -0.122027 -2.368536 H 0.136133 -1.319600 1.775606 H 0.576843 -3.660283 1.089854 H 0.602087 -2.484365 -3.034763 N 0.870138 -4.568228 -1.394770 O 0.960683 -5.439412 -0.479880 O 0.991147 -4.828752 -2.627707

o-nitrophenylsulfenyl (Nps)

Pd -0.584969 -1.647998 3.231751 S 0.637260 -2.047135 1.195181 O 2.171120 -1.588283 1.603982 O 0.419020 -3.377766 0.249707 C 0.043244 -0.629185 0.061644 C -0.556250 1.340655 -1.833466 C 0.034510 0.720820 0.424885 C -0.258886 -0.994152 -1.243980 C -0.570845 -0.011779 -2.193026 C -0.246245 1.712598 -0.524216 H -0.222944 -2.050270 -1.493127 H -0.810695 -0.304104 -3.209400 H -0.230535 2.751891 -0.221174 H -0.787473 2.105657 -2.565651 N 0.277351 1.195532 1.788978 O 0.848965 2.301450 1.939416 O -0.162628 0.522069 2.788495

3-nitro-2-napthylmethyl

Pd -0.786668 4.267333 0.360753 C 0.570482 2.886649 1.100944 H 0.525781 2.847524 2.191950 H 1.478346 3.381806 0.747658 C 0.291034 1.583021 0.476526 C 0.085207 0.462860 1.289391 C 0.064200 0.078969 -1.479678 C -0.096216 -0.843238 0.782904 C 0.229559 1.352639 -0.948940 C -0.084051 -1.044638 -0.643311 C -0.274033 -1.975859 1.632008 H -0.234522 -2.505881 -2.239153 H 0.023205 -0.029681 -2.556218 C -0.428475 -3.237213 1.097627 H -0.284867 -1.827000 2.707638 H -0.563559 -4.091908 1.752585 C -0.412492 -3.435050 -0.312578 H -0.532655 -4.436367 -0.712391 C -0.245615 -2.363831 -1.162720 H 0.100712 0.602281 2.366477 N 0.219147 2.439715 -1.885547 O 0.390658 3.665822 -1.449370 O -0.035178 2.222045 -3.116556

phenacyl

Pd 1.503194 -3.191223 -0.303476 C -0.395227 -2.562244 -0.843885 H -1.007402 -2.663677 0.055640 H -0.708618 -3.239330 -1.641645 C -0.189002 -1.186435 -1.347759 O -0.076476 -0.970884 -2.584876 C -0.074133 -0.038468 -0.385632 C 0.191862 2.187989 1.315933 C 0.095059 1.253312 -0.917679 C -0.113221 -0.198247 1.012323 C 0.022150 0.908208 1.856991 C 0.225094 2.357827 -0.075041 H 0.123421 1.359377 -1.996166 H -0.243244 -1.183135 1.447202 H -0.004482 0.771563 2.933518 H 0.353779 3.349207 -0.497832 H 0.297247 3.046161 1.972385

9-phenyl-9-fluorenyl (PhFl)

Pd -1.467194 0.441102 2.105029 C -0.344959 0.238619 0.316452 C -0.706866 -1.185595 0.082338 C -0.938367 -3.979235 -0.051128 C -1.880423 -1.762326 -0.433723 C 0.358082 -2.028624 0.530917 C 0.237111 -3.417301 0.467659 C -1.985550 -3.157161 -0.498972 H -2.701125 -1.137393 -0.770131 H 1.043401 -4.060148 0.808603 H -2.888286 -3.607754 -0.899453 H -1.038729 -5.058390 -0.110112 C 1.052951 0.190581 0.843104 C 3.602146 -0.455688 1.823476 C 1.451703 -1.173191 0.998571 C 1.960238 1.216351 1.145041 C 3.228697 0.885012 1.637869 C 2.715852 -1.491448 1.497313 H 1.695214 2.256647 0.992433 H 3.933279 1.676141 1.874887 H 3.018785 -2.527290 1.619031 H 4.589283 -0.691714 2.208227 C -0.834763 1.361462 -0.534903 C -1.738654 3.518077 -2.138551 C -0.836583 2.689923 -0.045537 C -1.288307 1.147855 -1.854830

C -1.735572 2.212407 -2.642781 C -1.283449 3.751513 -0.834929 H -0.503552 2.879222 0.970738 H -1.269487 0.145516 -2.267013 H -2.075043 2.021618 -3.656375 H -1.281489 4.759243 -0.430936 H -2.088343 4.341970 -2.752315 phenylsulfonyl

Pd -0.653014 -0.000002 3.935462 S 0.958086 0.000000 2.215995 O 1.759351 1.439652 2.373640 O 1.759350 -1.439652 2.373640 C 0.252267 0.000000 0.477286 C -0.810772 -0.000000 -2.067222 C 0.004424 -1.223817 -0.136006 C 0.004425 1.223817 -0.136006 C -0.537115 1.216128 -1.427228 C -0.537115 -1.216128 -1.427228 H 0.250164 -2.148085 0.374779 H 0.250165 2.148086 0.374779 H -0.734845 2.155826 -1.932024 H -0.734845 -2.155826 -1.932024 H -1.230526 -0.000000 -3.067845

2-phenylsulfonylethylcarbonyl (Psec)

Pd 2.851192 -1.784265 1.978822 C 3.796424 -0.015988 2.130295 O 4.435399 0.326367 3.116965 O 3.575953 0.989905 1.126178 C 3.034800 0.608755 -0.162264 H 3.517987 1.272957 -0.883390 H 3.303965 -0.425675 -0.414351 C 1.524058 0.829382 -0.237854 H 1.153732 1.436458 0.588921 H 1.194994 1.223717 -1.201684 S 0.543059 -0.823245 -0.127140 O 0.998041 -1.749224 -1.389550 O 0.693733 -1.405071 1.428239 C -1.251602 -0.384339 -0.338966 C -3.909449 0.231177 -0.699457 C -1.962276 0.119227 0.747045 C -1.817794 -0.614566 -1.589114 C -3.169424 -0.296603 -1.765255 C -3.311810 0.435581 0.551725 H -1.489498 0.236116 1.715569 H -1.220565 -1.047460 -2.384111 H -3.639805 -0.468919 -2.726987 H -3.894207 0.830328 1.376854 H -4.956906 0.475385 -0.840491

9-phenyl-9-xanthenyl (pixyl)

Pd -2.566116 0.000412 0.750960 C -0.562042 0.000179 0.079407 C -0.422754 -0.000085 -1.430662 C -0.065870 -0.000587 -4.233959 C 0.868946 -0.000720 -1.996060 C -1.527677 0.000282 -2.297404 C -1.352778 0.000039 -3.687438 C 1.046419 -0.000968 -3.382105 H 1.734297 -0.001025 -1.339928 H -2.528181 0.000730 -1.871041 H -2.221582 0.000327 -4.338372 H 2.050030 -0.001453 -3.796322 H 0.070765 -0.000784 -5.310814 C -0.160780 1.251336 0.775383 C 0.540782 3.604715 2.200186 C 0.290979 1.209979 2.116081 C -0.216079 2.526752 0.162033 C 0.121367 3.683079 0.862118 C 0.633042 2.359747 2.825765 H -0.535358 2.591745 -0.871883 H 0.060098 4.647010 0.367744 H 0.971635 2.256226 3.849805 H 0.803772 4.504257 2.746242 C -0.161273 -1.250903 0.775796 C 0.539286 -3.604074 2.201502 C 0.290502 -1.209291 2.116497 C -0.217117 -2.526494 0.162906

C 0.119849 -3.682704 0.863438 C 0.632095 -2.358945 2.826616 H -0.536416 -2.591730 -0.870987 H 0.058179 -4.646798 0.369393 H 0.970745 -2.255191 3.850591 H 0.801859 -4.503511 2.747923 O 0.426610 0.000437 2.804595 pivaloyl (Pv)

Pd -2.722241 -0.218289 1.439941 C -0.756786 -0.004304 1.409833 O -0.206546 0.050901 2.508699 C 0.010450 0.028646 0.058462 C 1.369523 0.733772 0.266203 H 1.947159 0.242205 1.054030 H 1.229926 1.781671 0.552951 H 1.945575 0.704717 -0.665863 C 0.231255 -1.451581 -0.356254 H 0.817938 -1.987972 0.397171 H 0.777907 -1.481601 -1.306163 H -0.723819 -1.971915 -0.488722 C -0.824565 0.757734 -1.013028 H -1.808391 0.286312 -1.130666 H -0.306976 0.720426 -1.978796 H -0.980409 1.809277 -0.747797

isopropyldimethylsilyl (IPDMS)

Pd -0.070082 0.592617 2.761311 Si -0.026544 0.592508 0.386604 C 0.926873 2.116049 -0.259844 H 1.960853 2.121563 0.101888 H 0.451745 3.048845 0.062701 H 0.952136 2.111578 -1.358764 C -1.814450 0.650033 -0.284133 H -1.809458 0.644848 -1.383433 H -2.329320 1.559136 0.045292 H -2.402079 -0.209261 0.055756 C 0.852562 -0.994679 -0.243632 H 1.913677 -0.932312 0.034086 H 0.822805 -0.965390 -1.345315 C 0.257991 -2.325499 0.257826 H 0.781989 -3.187099 -0.174768 H -0.802873 -2.418774 -0.005254 H 0.334175 -2.404163 1.349679

tetrahydropyran-2-yl (THP)

Pd -2.453545 0.456769 -2.352842 C -0.782311 0.025470 -1.291520 C 0.975108 1.247029 -0.113739 C 0.244745 -1.003920 0.770484 C 0.788734 0.389839 1.140830 C -1.044872 -0.870996 -0.085399 O -0.280831 1.323079 -0.885527 H 1.763191 0.824862 -0.757320 H 1.003664 -1.552988 0.193320 H 0.085008 0.893815 1.816083 H -1.840063 -0.432602 0.531703 H -0.084899 -0.438123 -2.012588 H 1.226548 2.283139 0.121230 H 0.040103 -1.592262 1.673777 H 1.747050 0.304573 1.671265 H -1.387629 -1.857684 -0.419756

thexyldimethylsilyl (TDS)

Pd -0.617611 1.302109 2.954532 Si -1.020082 1.060894 0.627579 C -0.527194 2.655438 -0.310590 H 0.535446 2.895610 -0.224279 H -1.098446 3.505976 0.078855 H -0.767922 2.553929 -1.378091 C -2.906818 0.887555 0.354526 H -3.127547 0.691860 -0.704512 H -3.409846 1.821065 0.631533 H -3.348272 0.081032 0.947347 C -0.107024 -0.540256 -0.063435 C 1.345000 -0.696633 0.531152 H 1.210037 -0.829683 1.617941 C -0.092359 -0.448354 -1.612601 H 0.542130 0.366669 -1.977521 H -1.103040 -0.283013 -2.007942 H 0.273717 -1.384102 -2.056193 C -0.962560 -1.765962 0.352146 H -0.549123 -2.694730 -0.060113 H -1.990087 -1.682657 -0.017974 H -1.006140 -1.871555 1.444129 C 2.097145 -1.945179 0.009826 H 3.065761 -2.032915 0.517448 H 2.298926 -1.872690 -1.065721 H 1.549687 -2.875402 0.190535 C 2.247402 0.541364 0.339666 H 3.244431 0.347778 0.754171 H 1.847460 1.424307 0.848948

H 2.376928 0.787544 -0.721363 triisopropylsilyloxycarbonyl (Tsoc)

Pd -0.341275 3.638126 -1.220002 C -0.173426 2.025865 -2.376852 O -0.074396 2.227916 -3.587569 O -0.196344 0.778346 -1.840169 Si -0.196433 -0.066958 -0.299249 C 0.099789 -1.891220 -0.829527 H -0.907828 -2.305186 -0.998129 C -1.962975 0.086836 0.439438 H -2.592162 -0.443194 -0.294453 C 1.235605 0.598317 0.792361 H 1.330621 -0.139867 1.605336 C -2.076572 -0.676323 1.782439 H -1.457857 -0.214459 2.562789 H -1.772883 -1.724895 1.687401 H -3.114147 -0.665479 2.140102 C -2.530626 1.516172 0.573824 H -2.015935 2.085664 1.356239 H -3.594343 1.477787 0.845548 H -2.451057 2.081956 -0.364211 C 0.976386 1.973197 1.444082 H 1.849124 2.290275 2.030243 H 0.107198 1.965777 2.109681 H 0.805152 2.747047 0.671688 C 2.571771 0.617348 0.011943 H 3.390082 0.944819 0.666499 H 2.524783 1.311979 -0.835260 H 2.834466 -0.369611 -0.383051

C 0.876905 -2.027475 -2.159931 H 1.910399 -1.675188 -2.057472 H 0.409791 -1.449105 -2.961152 H 0.915685 -3.081987 -2.464189 C 0.770899 -2.738172 0.280058 H 1.799806 -2.406949 0.466842 H 0.819599 -3.790495 -0.028688 H 0.230195 -2.700865 1.233391

2,2,2-trichloroethoxycarbonyl (Troc)

Pd -0.514755 -0.000000 3.167876 C 1.003936 0.000000 1.888426 O 2.121473 0.000000 2.392099 O 0.871097 -0.000000 0.504645 C -0.451885 -0.000000 -0.089752 H -1.008109 -0.895937 0.201039 H -1.008108 0.895937 0.201039 C -0.272347 -0.000000 -1.595550 Cl 0.624430 1.509444 -2.164592 Cl 0.624430 -1.509444 -2.164592 Cl -1.990161 0.000000 -2.340637

triethylsilyl (TES)

Pd 0.265337 -0.135860 2.661640 Si 0.314159 -0.154748 0.281871 C 1.189775 -1.745903 -0.351722 H 2.255284 -1.678760 -0.092479 H 1.142662 -1.724717 -1.453067 C 0.612246 -3.078251 0.165498 H 1.137347 -3.938075 -0.269512 H -0.451101 -3.182847 -0.082849 H 0.703485 -3.149819 1.256606 C -1.481166 -0.151690 -0.413565 H -1.402939 0.013541 -1.500629 H -1.881989 -1.167476 -0.290243 C -2.472414 0.860850 0.195479 H -2.143723 1.895779 0.046775 H -2.583104 0.704296 1.275920 H -3.467265 0.763833 -0.257975 C 1.331136 1.341688 -0.373156 H 2.379383 1.169196 -0.090536 H 1.304660 1.297395 -1.474462 C 0.895716 2.742896 0.099302 H 1.571743 3.519064 -0.281667 H 0.895324 2.808912 1.194452 H -0.114558 2.990695 -0.245682

trifluoroacetyl

Pd -0.551075 1.193406 2.019012 C -0.155142 0.868275 0.122382 O -0.114150 1.755677 -0.722787 C 0.129005 -0.597478 -0.274235 F -0.237302 -0.886838 -1.572689 F -0.555943 -1.470368 0.562927 F 1.484606 -0.862673 -0.134611 tri-n-hexylsilyl

Pd -0.688291 1.109695 2.653999 Si 0.631679 0.631291 0.737920 C 1.705300 2.158855 0.284941 H 2.441873 2.308689 1.087537 H 2.285222 1.900911 -0.617140

C 0.937756 3.475364 0.041717 H 0.326445 3.711879 0.926536 H 0.231219 3.346664 -0.791660 C -0.510668 0.205766 -0.752293 H 0.103656 -0.318671 -1.502968 H -0.817115 1.154176 -1.217603 C -1.770074 -0.634089 -0.443066 H -1.481953 -1.581392 0.034830 H -2.390609 -0.099446 0.292650 C -2.617516 -0.937148 -1.693118 H -1.998320 -1.473855 -2.428467 H -2.906213 0.012472 -2.169599 C -3.882586 -1.762683 -1.392759 H -3.593335 -2.713718 -0.919181 H -4.499589 -1.227289 -0.654568 C -4.731479 -2.058838 -2.642421 H -4.113724 -2.591625 -3.380414 H -5.021465 -1.108361 -3.114350 C -5.991759 -2.883616 -2.334282 H -5.730363 -3.857778 -1.902036 H -6.582292 -3.067522 -3.239563 H -6.635435 -2.362765 -1.614216 C 1.832224 -0.818276 1.130890 H 2.420043 -0.534069 2.015996 H 2.553203 -0.889231 0.298792 C 1.185324 -2.199342 1.363351 H 0.667491 -2.521843 0.448088 H 0.411215 -2.121181 2.141731 C 2.199654 -3.285838 1.771343 H 2.688617 -2.985116 2.710726 H 2.996584 -3.339223 1.013380 C 1.568676 -4.678811 1.945992 H 1.099445 -4.986111 0.998466 H 0.756003 -4.622127 2.686829 C 2.576724 -5.758553 2.382577 H 3.031071 -5.461077 3.339190 H 3.398243 -5.799596 1.652033 C 1.944227 -7.152086 2.524784 H 2.681776 -7.896953 2.845771 H 1.519427 -7.490638 1.571246 H 1.133342 -7.142864 3.264294 C 1.860598 4.670776 -0.263955 H 2.551863 4.815656 0.580380 H 2.487762 4.431468 -1.136753

C 1.097421 5.981511 -0.529301 H 0.456112 6.210347 0.336180 H 0.418962 5.840404 -1.384869 C 2.019774 7.182786 -0.806774 H 2.691880 7.326705 0.051955 H 2.665798 6.951262 -1.666616 C 1.247894 8.483730 -1.081031 H 1.928025 9.319511 -1.282993 H 0.623216 8.760051 -0.222180 H 0.587042 8.371759 -1.949950 triisopropylsilyl (TIPS)

Pd -1.561068 2.532456 1.159346 Si -0.372051 0.583725 0.458573 C 0.659357 -0.005561 1.995277 H -0.070050 -0.002261 2.821799 C 1.216509 -1.445851 1.891039 H 1.941674 -1.546553 1.074926 H 0.422173 -2.183499 1.728596 H 1.732584 -1.719119 2.822554 C 1.775966 0.994619 2.367847 H 2.543471 1.054264 1.585562 H 2.276747 0.688190 3.296551 H 1.375567 2.004994 2.519081 C -1.705483 -0.762200 0.024752 H -1.955862 -1.209917 1.001144 C -1.199937 -1.902477 -0.893091 H -0.293248 -2.381078 -0.508096 H -0.983280 -1.534390 -1.903271 H -1.970907 -2.680488 -0.989044 C -3.014720 -0.166035 -0.546136

H -2.854031 0.300008 -1.526349 H -3.430908 0.600392 0.120568 H -3.771444 -0.953058 -0.674064 C 0.752116 1.146674 -1.026114 H 1.279098 2.032200 -0.636293 C 1.834725 0.132857 -1.470100 H 2.510345 -0.135162 -0.650691 H 2.447071 0.567317 -2.273419 H 1.392436 -0.790848 -1.859739 C -0.086098 1.607401 -2.240317 H 0.561408 2.042879 -3.014027 H -0.829467 2.363277 -1.958549 H -0.622691 0.767245 -2.698315 triisopropylsilyloxymethyl (TOM)

Pd -0.547478 3.128074 1.348416 C -0.573025 2.359615 -0.533803 H 0.436978 2.497675 -0.945932 H -1.325423 2.937455 -1.078491 O -0.977160 1.001927 -0.506149 Si -0.069941 -0.406625 -0.029173 C 1.691501 -0.285593 -0.711942 H 2.263008 -1.182839 -0.445080 H 2.226254 0.579363 -0.303176 H 1.694039 -0.199236 -1.804085 C -1.024764 -1.843967 -0.781439 H -0.573591 -2.804407 -0.504518 H -1.042446 -1.778036 -1.874256 H -2.061732 -1.842375 -0.429009 C -0.034488 -0.523031 1.856194 H 0.529858 -1.404542 2.184236

H -1.048991 -0.597588 2.262850 H 0.437402 0.364130 2.295359 trimethylsilyl (TMS)

Pd 0.004922 0.001240 -2.842367 Si -0.001836 0.000084 -0.468937 C 0.899066 -1.556597 0.173365 H 0.906730 -1.567277 1.272484 H 1.938175 -1.583643 -0.172312 H 0.405209 -2.471800 -0.170708 C 0.899341 1.556610 0.173372 H 0.907581 1.567263 1.272478 H 0.405494 2.471909 -0.170454 H 1.938278 1.583484 -0.172843 C -1.799820 -0.000219 0.173680 H -1.813481 0.000808 1.272858 H -2.344204 -0.886619 -0.169475 H -2.345454 0.884758 -0.171140

2-(trimethylsilyl)ethanesulfonyl (SES)

Pd 4.214395 -1.378174 -2.494784 S 2.204533 -1.053238 -1.316402 O 1.293894 -2.381976 -1.695401 O 2.719377 -0.860346 0.253201 C 1.096005 0.495765 -1.722228 H 1.613198 1.299135 -1.193749 H 1.221531 0.600770 -2.803847 C -0.347865 0.272977 -1.296149 H -0.729677 -0.633380 -1.783246 H -0.924768 1.114412 -1.711776 Si -0.769841 0.196974 0.587727 C -2.626888 0.597037 0.701014 H -2.975599 0.544298 1.739210 H -3.221287 -0.115187 0.115816 H -2.845593 1.604777 0.327034 C -0.435574 -1.523420 1.304939 H 0.637231 -1.741023 1.296457 H -0.943286 -2.304229 0.728108 H -0.788616 -1.580605 2.342210 C 0.244761 1.512597 1.507326 H 1.308677 1.250911 1.487408 H -0.064030 1.571455 2.557887 H 0.119423 2.510470 1.069242

2-(trimethylsilyl)ethoxycarbonyl (Teoc)

Pd 0.283066 4.067588 2.334967 C 0.275882 3.347468 0.482911 O -0.056506 4.133298 -0.402866 O 0.608045 2.046876 0.188514 C 1.007424 1.116957 1.275324 H 1.905822 1.524309 1.753263 H 0.195738 1.082658 2.010734 C 1.249484 -0.245033 0.639750 H 2.150446 -0.203903 0.013958 H 1.462418 -0.958591 1.448994 Si -0.206223 -0.946665 -0.408128 C -0.218275 -0.188915 -2.145517 H 0.717359 -0.405577 -2.674511 H -0.327234 0.897974 -2.084622 H -1.042854 -0.590424 -2.746764 C -1.846657 -0.600388 0.489392 H -1.847367 -1.023200 1.501508 H -2.686417 -1.047813 -0.055611 H -2.037833 0.475956 0.566258 C 0.062292 -2.827036 -0.526861 H 1.022670 -3.061914 -1.001968 H -0.726855 -3.299261 -1.123918 H 0.055578 -3.294365 0.465192

2-(trimethylsilyl)ethoxymethyl (SEM)

Pd -1.081630 4.518203 1.455467 C -0.492340 3.938059 -0.403661 H 0.604977 4.015399 -0.440052 H -0.985576 4.614316 -1.106165 O -0.955674 2.622004 -0.678676 C -0.166121 1.527877 -0.095810 H 0.877463 1.642556 -0.426389 H -0.193000 1.625027 0.998374 C -0.767633 0.212224 -0.561050 H -0.791746 0.202958 -1.659280 H -1.814158 0.164710 -0.230862 Si 0.138057 -1.365312 0.040046 C -0.833893 -2.868294 -0.596538 H -0.355684 -3.806363 -0.290579 H -0.896639 -2.867026 -1.691180 H -1.857799 -2.871030 -0.204045 C 1.907705 -1.404516 -0.656161 H 2.416854 -2.333275 -0.371772 H 2.512071 -0.569516 -0.282209 H 1.903726 -1.349971 -1.751360 C 0.198377 -1.402931 1.940439 H 0.690176 -2.316235 2.296143 H -0.810637 -1.380150 2.368826 H 0.753125 -0.548713 2.346492

2-(trimethylsilyl)ethyl (TMSE)

Pd 3.016081 0.679747 0.977854 C 2.291027 0.118249 -0.858025 H 2.377657 -0.976178 -0.872224 H 3.017085 0.553973 -1.558620 C 0.860515 0.602425 -1.112028 H 0.545482 0.273454 -2.121556 H 0.830012 1.701036 -1.141935 Si -0.495931 -0.015018 0.095659 C -0.218778 0.661000 1.853046 H 0.755307 0.342048 2.253754 H -0.992288 0.298906 2.541664 H -0.243265 1.757233 1.865870 C -2.179302 0.613988 -0.528624 H -2.412216 0.216821 -1.523546 H -2.189554 1.708772 -0.593727 H -2.987666 0.313682 0.148893 C -0.493156 -1.916147 0.137166 H -0.689373 -2.332320 -0.858350 H -1.265151 -2.297152 0.816348 H 0.473512 -2.304518 0.478381

triphenylsilyl (TPS)

Pd -0.501048 0.000042 3.311896 Si -0.097210 0.000025 0.983012 C 0.853839 -1.569983 0.465728 C 2.326909 -3.853538 -0.330427 C 0.769319 -2.068342 -0.852456 C 1.695561 -2.246590 1.371537 C 2.424901 -3.375782 0.981203 C 1.497898 -3.196417 -1.247239 H 0.127299 -1.574908 -1.576924 H 1.777456 -1.886358 2.394250 H 3.065569 -3.880847 1.697969 H 1.417909 -3.561493 -2.267037 H 2.890456 -4.730009 -0.635621 C -1.823809 0.000010 0.193277 C -4.472940 -0.000037 -0.810337 C -2.508270 1.209462 -0.061183 C -2.508240 -1.209467 -0.061173 C -3.815288 -1.210622 -0.559572 C -3.815321 1.210569 -0.559581 H -2.012722 2.157181 0.128702 H -2.012668 -2.157171 0.128723 H -4.319901 -2.153245 -0.750253 H -4.319961 2.153175 -0.750275 H -5.488220 -0.000054 -1.195264 C 0.853916 1.569987 0.465696 C 2.326969 3.853613 -0.330355 C 1.695521 2.246656 1.371570 C 0.769643 2.068237 -0.852548 C 1.498124 3.196406 -1.247248 C 2.424875 3.375858 0.981280

H 1.777341 1.886447 2.394299 H 0.127916 1.574679 -1.577172 H 1.418200 3.561468 -2.267057 H 3.065485 3.880938 1.698086 H 2.890491 4.730112 -0.635508

4-4'-4''-tris(benzoyloxy)trityl (TBTr)

Pd 0.804418 -2.877753 -0.488840 C 0.539197 -0.777545 -0.278323 C 1.384585 -0.525207 0.939677 C 2.969465 -0.139008 3.249377 C 2.473613 0.376608 0.943524 C 1.099576 -1.195349 2.157584 C 1.872632 -1.007798 3.301159 C 3.261865 0.564720 2.080242 H 2.702075 0.944158 0.049880 H 0.250996 -1.870110 2.200799 H 1.623110 -1.528292 4.218542 H 4.091930 1.261852 2.078560 C 1.075999 -0.292150 -1.598202 C 2.095078 0.550250 -4.097004 C 2.381656 -0.650958 -2.025821 C 0.315395 0.517951 -2.469424 C 0.807413 0.928348 -3.711349 C 2.886233 -0.241248 -3.256752 H 2.997609 -1.270540 -1.381684

H -0.679372 0.829876 -2.176346 H 0.189812 1.532286 -4.366545 H 3.876147 -0.534176 -3.586567 C -0.952504 -0.674162 -0.090266 C -3.757168 -0.530742 0.230411 C -1.838988 -1.285083 -1.009381 C -1.531294 0.037060 0.984866 C -2.914119 0.105972 1.145819 C -3.226382 -1.229136 -0.862879 H -1.429092 -1.825650 -1.857589 H -0.893442 0.546126 1.697240 H -3.353395 0.654670 1.970860 H -3.877074 -1.721090 -1.568664 O 3.770011 0.138655 4.374995 O 2.642627 0.870844 -5.353867 O -5.131839 -0.371841 0.520013 C -6.189780 -0.967617 -0.151761 C 4.009700 -0.783098 5.414751 C 2.291604 2.016688 -6.098458 O 3.907767 -0.385543 6.572910 O 2.007074 1.869909 -7.284526 O -6.045986 -1.727647 -1.118100 C -7.493917 -0.578444 0.428624 C -10.017417 0.092135 1.439952 C -8.655231 -1.103694 -0.166339 C -7.601780 0.283507 1.534012 C -8.862504 0.615645 2.035201 C -9.911876 -0.767844 0.338630 H -8.550243 -1.767143 -1.017178 H -6.703747 0.683257 1.987014 H -8.945006 1.281160 2.888183 H -10.806050 -1.173649 -0.122790 H -10.995292 0.353316 1.832104 C 4.449538 -2.150237 5.038426 C 5.330221 -4.752087 4.478834 C 4.335303 -3.161597 6.010082 C 5.026367 -2.446482 3.790657 C 5.467028 -3.743619 3.516545 C 4.765330 -4.458499 5.726927 H 3.911407 -2.911866 6.976270 H 5.141097 -1.668757 3.045361 H 5.919086 -3.966308 2.555732 H 4.665325 -5.236612 6.476256 H 5.667422 -5.760020 4.259168

C 2.379484 3.332789 -5.417663 C 2.551218 5.887243 -4.277405 C 1.742723 4.427178 -6.031752 C 3.117456 3.529786 -4.236923 C 3.202500 4.804832 -3.672750 C 1.822624 5.696914 -5.459082 H 1.195775 4.262559 -6.953296 H 3.629417 2.696512 -3.771475 H 3.778083 4.954862 -2.765369 H 1.323165 6.535775 -5.932226 H 2.615341 6.875160 -3.832588 tosyl (Ts)

Pd -0.715432 0.000005 4.622090 S 0.967537 -0.000001 2.973756 O 1.755047 1.440148 3.192795 O 1.755042 -1.440152 3.192796 C 0.400757 -0.000000 1.189893 C -0.436396 -0.000000 -1.464178 C 0.204868 1.220328 0.552210 C 0.204869 -1.220328 0.552209 C -0.218704 -1.210250 -0.780229 C -0.218705 1.210249 -0.780228 H 0.400330 2.147838 1.078652 H 0.400332 -2.147838 1.078651 H -0.372909 -2.152763 -1.296937 H -0.372911 2.152762 -1.296935 C -0.860330 0.000000 -2.915496 H 0.015027 0.000001 -3.579157 H -1.454211 0.886551 -3.159945 H -1.454209 -0.886552 -3.159946

trityl (Tr)