Catalytic Stereoselective Installation of Boron Via C–C Bond Formation and Stereoselective Synthesis of N-Heterocyclic Scaffolds Via Main Group Lewis Acid Catalysis Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 20, 2019
  • Moyer, Brandon
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Enantiomerically pure chiral boron-containing molecules provide enabling platforms for chemical synthesis in that they are configurationally stable, they function as useful synthons for various functional groups, and their transformations into those diverse functionalities are stereospecific. With consensus that chiral alkyl sp3 C–B bond-containing compounds are desirable building blocks, and given that most enantioselective preparations to date focus on installing a stereodefined C–B bond, our group sought to develop catalytic methods to generate and use chiral α-boron-containing nucleophiles that would enable the direct formation of a new C–C bond. To this extent, we exploited the utility of alkyl 1,1-diboron reagents, which have been shown to readily undergo facile activation and transmetalation in the presence of alkoxide bases to form chiral α-boryl nucleophiles. The result of these investigations was the development of the first catalytic enantio- and diastereoselective synthesis of syn-1,2-hydroxyboronates via addition to aldehydes (Ch. 1). The reactions are promoted by a readily available chiral monodentate phosphoramidite–Cu(I) complex in the presence of an alkyl 1,1-diboron reagent. The products contain two contiguous stereogenic centers and are obtained in up to 91% yield, >98:2 d.r., and 98:2 e.r. The reaction is tolerant of aryl and vinyl aldehydes, and the 1,2-hydroxyboronate products can be transformed into versatile derivatives. Mechanistic experiments indicate that control of absolute stereochemistry resides at the α-boryl component. Further investigations resulted in the development of a substantially more reactive Ag(I) catalytic protocol for the diastereoselective synthesis of complementary anti-1,2-hydroxyboronates with up to 99:1 d.r. (Ch. 2). We found that the increased reactivity of Ag(I), in conjunction with stoichiometric KOtBu, allowed for a substantial broadening of substituted 1,1-diboronates that participate in the reaction. In addition, alkyl aldehydes were found to be suitable electrophiles with n-BuLi as an activator. BRANDON S. MOYER: STEREOSELECTIVE SYNTHESIS OF N-HETEROCYCLIC SCAFFOLDS VIA MAIN GROUP LEWIS ACID CATALYSIS (Under the guidance of Michel R. Gagné) Silylium ions (formally [R3Si]+) have long been the subject of investigations and significant debate in both theoretical and experimental chemistry, but few catalytic, synthetic applications have been reported due to the exceptionally high reactivity and Lewis acidity of these elusive species. Chapter 3 discusses the application of easily accessible silylium ion catalysts to the stereoselective synthesis of various N-heterocyclic pyrrolidine and piperidine scaffolds. The tested substrates are derived from the chiral pool and can be obtained in three high-yielding steps from amino alcohols; subsequent stereoselective silylium ion-catalyzed Prins-cyclization and trapping with R3Si–Nu nucleophiles (e.g. Nu = H, allyl, azide, and enol ethers) results in novel nitrogen-containing polycyclic scaffolds with potential medicinal chemistry applications. An appendix to this chapter (A) discusses the substrate scope of the unpublished discovery that the Lewis acid B(C6F5)3 catalyzes a stereospecific Prins cyclization followed by an elimination (formally a carbonyl-ene reaction) to form trans-tetrahydropyridine products in exceptionally high yield and diastereoselectivity.
Date of publication
Resource type
Rights statement
  • In Copyright
  • Brustad, Eric
  • Alexanian, Erik
  • Leibfarth, Frank
  • Gagne, Michel
  • Johnson, Jeffrey
  • Meek, Simon
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017

This work has no parents.