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

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Assessing Steric Bulk of Protecting Groups Via a Computational Determination of Exact Cone Angle and Exact Solid Cone Angle 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 by 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 ii 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 iv 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 v 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 1 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 2 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 3 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
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