I. The first highly enantioselective organocatalytic Diels-Alder reaction. II. Development of antibiotics against vancomycin-resistant bacteria. III. Annulation of aromatic imines via directed carbon-hydrogen bond activation

A general strategy for asymmetric catalysis using purely organic reagents and its application to the Diels-Alder reaction is described in Chapter 1. This organocatalytic strategy is based on LUMO-lowering activation of α,β-unsaturated aldehydes via the reversible formation of iminium ions. Preliminary mechanistic data are consistent with this mode of substrate activation. The development of an imidazolidinone catalyst enabled Diels-Alder cycloadditions of various dienes and dienophiles in high enantioselectivities, and provided a platform for extension of this catalytic strategy to a range of other asymmetric transformations.; The glycopeptide antibiotic vancomycin is used clinically as a last line of defense for the treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus strains and multiply resistant Streptococcus pneumoniae strains. Consequently, the emergence of bacterial resistance to vancomycin poses a serious threat towards the effective treatment of bacterial infections. Chapter 2 describes the synthesis of dimeric vancomycin analogues based on a lead compound from a library of ∼27,000 synthetic analogues of vancomycin. These synthetic compounds were up to 60-fold more active than vancomycin against vancomycin-resistant Enterococcus faecium (VRE, VanA phenotype).; In contemporary organic synthesis, one of the most attractive methods for carbon-carbon bond formation is the transition metal-catalyzed activation and functionalization of otherwise unreactive carbon-hydrogen bonds. Chapter 3 describes the synthesis of functionalized indanes, tetralanes, dihydrobenzofurans, dihydroindoles, and other polycyclic compounds from simple starting materials using directed C–H bond activation. The annulation of aromatic ketimines and aldimines, in which an alkene is tethered at the meta position, proceeds via imine-directed C–H bond activation followed by olefin addition to the most hindered ortho site. The cyclizations generally proceed with high selectivity, and the reactions are tolerant of various functional groups, different tether lengths, and a number of alkene substitution patterns.; To date, only a few examples of C–H bond activation in the synthesis of natural products or biologically active molecules have been reported. Chapter 4 illustrates the synthesis of a conformationally restricted tetrahydrobis(benzofuran) mescaline analog in six steps and 38% overall yield from (4′ -O-methyl)methyl gallate, in which the key step is a rhodium-catalyzed tandem C–H activation/C–C bond forming reaction.