New Concepts, Catalysts, and Methods for Enantioselective Synthesis of C-B and C-C Bonds

Thesis advisor: Amir H. HoveydaChapter 1. Part A: N-Heterocyclic Carbenes Catalyzed Enantioselective Boryl Conjugate Additions to α,β-Unsaturated Ketones, Esters, Weinreb Amides and Aldehydes. The first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls are reported. Transformations are promoted by 5.0 mol % of a chiral Lewis basic N-heterocyclic carbene. The distinctive feature of the reactions in chemoselectivity of the method compared to the Cu-catalyzed variants has been illustrated. Part B: Enantioselective Synthesis of Boron-Substituted Quaternary Carbon Stereogenic Centers through N-Heterocyclic Carbenes Catalyzed Boryl Conjugate Additions to Cyclic and Acyclic Enones The first examples of Lewis base catalyzed enantioselective boryl conjugate additions that afford products containing boron-substituted quaternary carbon stereogenic centers are presented. The carbon–boron bond forming reactions are promoted by 1.0–5.0 mol % of a chiral N–hererocyclic carbene. Cyclic or linear α,β–unsaturated ketones can be used as suitable substrates and the desired products are obtained in 63–95% yield and 91:9 to >99:1 enantiomeric ratio. The utility of the Lewis base-catalyzed approach is demonstrated in the context of an enantioselective formal synthesis of antifungal natural product crassinervic acid. Chapter 2. Enantioselectivity Fluctuations in Phosphine–Cu-Catalyzed Enantioselective Boron-Allyl Addition to Aryl-Substituted Olefins. Catalytic enantioselective multicomponent processes involving B2(pin)2, aryl or heteroaryl monosubstituted olefins, and allylic phosphates or carbonates are disclosed. Transformations promoted by a chiral Cu–phosphine complex afford products that contain a primary C–B(pin) bond and an allyl-substituted tertiary carbon stereogenic center in up to 84% yield and 98:2 enantiomeric ratio. The utility of the approach is showcased in the enantioselective formal synthesis of biologically active heliespirones A and C. Based on mechanistic and computational studies, we show that enantioselectivities variations can depend on electronic and/or steric factors of the alkene substrate and the allyl electrophile as well as their concentration. In most cases, selectivity loss can be minimized and that the resulting insights are also applicable to reactions involving Cu–H species. Chapter 3. Synthesis of Vicinal Diboronate Compounds through Practical Phosphine–Copper Catalyzed Three-Component Processes. The phosphine–Cu-catalyzed multicomponent processes have been developed for a practical and direct synthesis of vicinal diboronate compounds. Reactions of alkenyl–boronates, allylic phosphates, and diboron reagents are promoted by 2.5–10 mol % of a Cy3P–Cu complex affording a wide range of desirable vicinal diboronate products. The ability for easy access to either regioisomers of the products with a C–B(pin) and an adjacent C–B(dan) bond that can be site-selectively functionalized is a noteworthy feature of the method.Thesis (PhD) — Boston College, 2016.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Chemistry

Catalyst-Controlled Stereoselective Olefin Metathesis as a Principal Strategy in Multistep Synthesis Design: A Concise Route to (+)-Neopeltolide

Molybdenum-, tungsten-, and ruthenium-based complexes that control the stereochemical outcome of olefin metathesis reactions have been recently introduced. However, the complementary nature of these systems through their combined use in multistep complex molecule synthesis has not been illustrated. A concise diastereo- and enantioselective route that furnishes the anti-proliferative natural product neopeltolide is now disclosed. Catalytic transformations are employed to address every stereochemical issue. Among the featured processes are an enantioselective ring-opening/cross-metathesis promoted by a Mo monoaryloxide pyrrolide (MAP) complex and a macrocyclic ring-closing metathesis that affords a trisubstituted alkene and is catalyzed by a Mo bis(aryloxide) species. Furthermore, Z-selective cross-metathesis reactions, facilitated by Mo and Ru complexes, have been employed in the stereoselective synthesis of the acyclic dienyl moiety of the target molecule.National Institutes of Health (U.S.) (NIH grant GM-59426)National Institutes of Health (U.S.) (NIH grant GM-57212)AstraZeneca (Firm) (Graduate Fellowship)National Science Foundation (U.S.) (NSF award CHE-1362763

Switchable synthesis of Z-homoallylic boronates and E-allylic boronates by enantioselective copper-catalyzed 1,6-boration

The enantioselective Cu-catalyzed 1,6-boration of (E,E) α,β,γ,δ-unsaturated ketones is described, which gives homoallylic boronates with high enantiomeric purity and unexpectedly high Zselectivity. By changing the solvent, the outcome can be altered to give E-allylic boronates

An Improved Scalable Process for the Synthesis of (S,S)-DACH-Ph Trost Ligand

AbstractAn improved chemical process has been developed for the synthesis of (S,S)-DACH-Ph Trost ligand. The amidation of 2-diphenylphosphinylbenzoic acid and (S,S)-diaminocyclohexane is promoted by stoichiometric CDI and catalytic imidazole hydrochloride. The resulting product, (S,S)-DACH-Ph Trost ligand, is isolated as a white solid in 80% yield with &gt;99% ee by simple filtration without column chromatography. The current facile process is also demonstrated on kilogram scale.</jats:p