Thesis advisor: Amir H. Hoveyda / Chapter 1. A Review of Sulfonate-Containing NHC Ligands in Copper-Catalyzed Enantioselective Transformations—Maneuvering Selectivities in Tight Space. A comprehensive review of enantioselective copper-catalyzed transformations, which are promoted by a chiral N-heterocyclic carbene metal complex that features a unique sulfonate motif, is provided in this chapter. Reactions have been categorized into four sets: allylic substitutions conjugate additions, Cu-B additions alkenes and multicomponent reactions. The mechanistic scenarios provided by DFT calculations accounts for their uniquely reaction profile in enantioselective allylic substitutions (EAS), enantioselective conjugate additions (EAS) and enantioselective Cu-B additions to alkenes. Mechanistic investigations (density functional theory calculations and deuterium labeling) point to a bridging function for an alkali metal cation connecting the sulfonate anion and a substrate’ s phosphate group to form the branched addition products as the dominant isomers via Cu(III) π -allyl intermediate complexes in EAS reactions. Sulfonate-bearing NHC ligand with different substitution patterns promote EAS reactions with different reactivity and enantioselectivity. We also developed a guideline to follow to choose the proper sulfonate-based NHC ligands according to the combination of the substrates and the nucleophiles. Chapter 2. NHC–Cu-Catalyzed Enantioselective Allylic Substitutions with Silyl-protected Propargyl Boron Reagent to Generate Tertiary and Quaternary Carbon Stereogenic Centers. Catalytic allylic substitution reactions involving a propargylic nucleophilic component are presented; reactions are facilitated by 5.0 mol % of a catalyst derived from a chiral N-heterocyclic carbene (NHC) and a copper chloride salt. A silyl-containing propargylic organoboron compound, easily prepared in multi-gram quantities, serves as the reagent. Aryl- and heteroaryl-substituted disubstituted alkenes within allylic phosphates and those with an alkyl or a silyl group can be used. Functional groups typically sensitive to hard nucleophilic reagents are tolerated, particularly in the additions to disubstituted alkenes. Reactions may be performed on the corresponding trisubstituted alkenes, affording quaternary carbon stereogenic centers. Incorporation of the propargylic group is generally favored (vs allenyl addition; 89:11 to >98:2 selectivity); 1,5-enynes can be isolated in 75−90% yield, 87:13 to >98:2 SN2′:SN2 (branched/linear) selectivity and 83:17−99:1 enantiomeric ratio. Utility is showcased by conversion of the alkynyl group to other useful functional units. Application to stereoselective synthesis of the acyclic portion of antifungal agent plakinic acid A, containing two remotely positioned stereogenic centers, by sequential use of two different NHC–Cu-catalyzed enantioselective allylic substitution (EAS) reactions further highlights utility. Chapter 3. NHC–Cu-Catalyzed Enantioselective Allylic Substitutions with Methylenediboron to Generate Tertiary and Quaternary Carbon Stereogenic Centers. A catalytic EAS method for the site- and enantioselective addition of commercially available di-B(pin)-methane to disubstituted allylic phosphates is introduced. Transformations are facilitated by a sulfonate-containing NHC–Cu complex and products are obtained in 63–95% yield, 88:12 to >98:2 SN2’/SN2 selectivity, and 85:15–99:1 enantiomeric ratio. The utility of the approach is highlighted by its application to the formal synthesis of the cytotoxic natural product rhopaloic acid A, in an all-catalytic-method synthesis route. Catalytic EAS methods of the di-B(pin) methane to Z-trisubstituted allylic phosphates are also disclosed and DFT calculations provide insights to the stereochemical models for those transformations and rationales for the choice of Z-trisubstituted allylic phosphates as the starting materials. Chapter 4. Enantioselective NHC–Cu-Catalyzed Prenyl Conjugate Additions to Enoates to Generate Tertiary Carbon Stereogenic Centers. An efficient catalytic protocol for generation of prenyl-bearing tertiary carbon stereogenic centers from aryl-substituted enoates was achieved in the presence of a chiral alkoxy-based NHC–Cu complex. A range of aryl and heteroaryl-substituted substrate were suitable substrates, the corresponding prenyl conjugate addition products were generated in up to 94% yield and 95:5 enantioselectivity. The utility of the current method has been shown in the application to the synthesis of a selective integrin antagonist. DFT calculations provided a stereochemical model for the ECA reaction employing alkoxy-containing NHC–Cu catalyst. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.
| Identifer | oai:union.ndltd.org:BOSTON/oai:dlib.bc.edu:bc-ir_107648 |
| Date | January 2017 |
| Creators | Shi, Ying |
| Publisher | Boston College |
| Source Sets | Boston College |
| Language | English |
| Detected Language | English |
| Type | Text, thesis |
| Format | electronic, application/pdf |
| Rights | Copyright is held by the author, with all rights reserved, unless otherwise noted. |
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