Progress toward the synthesis of the complestatins, novel HIV-1 entry inhibitors from soil bacteria

The binding of human cluster determinant 4 (CD4) to the human immunodefeciency virus type 1 (HIV-1) envelope glycoprotein gp120 represents the first step in viral entry and, thus, HIV infection. The binding of CD4 to gp120 induces major conformational alterations in the viral protein, unveiling a secondary binding epitope, which then binds with either CCR5 or CXCR4 chemokine receptors. The vital role of CD4-gp120 binding in HIV infection has marked this interaction as a target for pharmaceutical intervention. Through a combination of literature review and collaborative studies, the first chapter of this dissertation presents a working hypothesis for the future development of CD4-gp120 binding agonists and antagonists. The second chapter focuses on progress toward the synthesis of a family of known CD4-gp120 inhibitors, the complestatins. In particular, a stereodivergent synthesis of four diastereomers of the complestatin western (BCD) macrocycle, including the natural configuration, is described. The strategy takes advantage of a ruthenium-activated intramolecular SNAr diaryletherification. Also, novel methods for constructing various substituted phenylglycines in enantiopure form are described. The configuration of the two phenylglycine units of the BCD macrocycle were found to have a remarkable effect in directing the overall peptide backbone conformation

High π‑Facial and <i>exo</i>-Selectivity for the Intramolecular Diels–Alder Cycloaddition of Dodeca-3,9,11-trien-5-one Precursors to 2-<i>epi</i>-Symbioimine and Related Compounds

An unconstrained exocyclic stereogenic center and a removable trimethylsilyl group are combined to induce high π-facial selectivity and near-exclusive <i>exo</i>-selectivity in the intramolecular Diels–Alder cycloaddition of dodeca-3,9,11-trien-5-ones. This strategy provides direct access to polysubstituted <i>trans</i>-1-decalones related to the symbioimines in good yield and acceptable diastereoselectivity

Decarboxylative Generation of 2‑Azaallyl Anions: 2‑Iminoalcohols via a Decarboxylative Erlenmeyer Reaction

Condensation between the tetrabutylammonium salt of 2,2-diphenylglycine and aldehydes results in a decarboxylative Erlenmeyer reaction, affording 1,2-diaryl-2-iminoalcohols as a mixture of diastereomers in good yields. The diastereomeric ratio shifts over time, with the <i>anti</i> diastereomer and the <i>syn</i> oxazolidine tautomer serving as the kinetic and thermodynamic products, respectively. Addition of Lewis acids can catalyze the rates of reaction and product equilibration. The results highlight the stereochemical promiscuity of 1,2-diaryl-2-iminoalcohols in the presence of Lewis acids and Brønsted bases

Localized Changes in the gp120 Envelope Glycoprotein Confer Resistance to Human Immunodeficiency Virus Entry Inhibitors BMS-806 and #155

BMS-806 and the related compound, #155, are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor, CD4. We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound conformation of gp120, the amino acid residues implicated in BMS-806 and #155 resistance line the “phenylalanine 43 cavity” and a water-filled channel that extends from this cavity to the inner domain. Structural considerations suggest a model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs

Exploring the Steric and Electronic Factors Governing the Regio- and Enantioselectivity of the Pd-Catalyzed Decarboxylative Generation and Allylation of 2‑Azaallyl Anions

The impact of the steric and electronic factors in both the <i>para</i>-substituted benzaldimine and 2,2-diarylglycine components on the regioselectivity and enantioselectivity of the palladium-catalyzed decarboxylative allylation of allyl 2,2-diarylglycinate aryl imines was explored. These studies revealed that using 2,2-di­(2-methoxyphenyl)­glycine as the amino acid linchpin allowed for the exclusive synthesis of the desired homoallylic benzophenone imine regioisomers, independent of the nature of the imine moiety, in typically high yields. The resulting enantiomeric ratios, however, are slightly decreased in comparison to the transformations involving the corresponding allyl 2,2-diphenylglycinate imines, but this is more than balanced out by the increases in yield and regioselectivity. Overall, these studies suggest a general strategy for the highly regioselective functionalization of 2-azaallyl anions

Palladium-Catalyzed Decarboxylative Generation and Asymmetric Allylation of α‑Imino Anions

A palladium-catalyzed asymmetric decarboxylative allylic alkylation of allyl 2,2-diphenylglycinate imines using (<i>S,S</i>)-<i>f</i>-binaphane as a chiral supporting ligand has been developed. This transformation allows for decarboxylative generation and enantioselective allylation of nonenolate α-imino (2-azaallyl anions) to afford α-aryl homoallylic imines