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

Enantiodifferentiation in the Photoisomerization of (<i>Z</i>,<i>Z</i>)‑1,3-Cyclooctadiene in the Cavity of γ‑Cyclodextrin–Curcubit[6]uril-Wheeled [4]Rotaxanes with an Encapsulated Photosensitizer

A biphenyl photosensitizer axle was implanted into the cavities of native and capped γ-cyclodextrins through rotaxanation using a cucubit[6]­uril-templated azide–alkyne 1,3-dipolar cycloaddition, resulting in the construction of highly defined chiral binding/sensitizing sites. The orientation and interaction of the axle and capping moieties at the ground and excited states were interrogated by NMR, UV–vis, circular dichroism, and fluorescence spectroscopic studies. In situ photoisomerization of (<i>Z</i>,<i>Z</i>)-1,3-cyclooctadiene sensitized in the cavity of these [4]­rotaxanes afforded (<i>Z</i>,<i>E</i>)-1,3-cyclooctadiene in up to 15.3% ee, which represents the highest level of enantiodifferentiation obtained to date for this supramolecular photochirogenesis

Transition-Metal-Free Radical C(sp³)–C(sp²) and C(sp³)–C(sp³) Coupling Enabled by 2‑Azaallyls as Super-Electron-Donors and Coupling-Partners

The past decade has witnessed the rapid development of radical generation strategies and their applications in C–C bond-forming reactions. Most of these processes require initiators, transition metal catalysts, or organometallic reagents. Herein, we report the discovery of a simple organic system (2-azaallyl anions) that enables radical coupling reactions under transition-metal-free conditions. Deprotonation of <i>N</i>-benzyl ketimines generates semistabilized 2-azaallyl anions that behave as “super-electron-donors” (SEDs) and reduce aryl iodides and alkyl halides to aryl and alkyl radicals. The SET process converts the 2-azaallyl anions into persistent 2-azaallyl radicals, which capture the aryl and alkyl radicals to form C–C bonds. The radical coupling of aryl and alkyl radicals with 2-azaallyl radicals makes possible the synthesis of functionalized amine derivatives without the use of exogenous radical initiators or transition metal catalysts. Radical clock studies and 2-azaallyl anion coupling studies provide mechanistic insight for this unique reactivity

Supramolecular Photochirogenesis Driven by Higher-Order Complexation: Enantiodifferentiating Photocyclodimerization of 2‑Anthracenecarboxylate to Slipped Cyclodimers via a 2:2 Complex with β‑Cyclodextrin

Chiral slipped 5,8:9′,10′-cyclodimers were preferentially produced over classical 9,10:9′,10′-cyclodimers upon supramolecular photocyclodimerization of 2-anthracenecarboxylate (AC) mediated by β-cyclodextrin (β-CD). This photochirogenic route to the slipped cyclodimers, exclusively head-to-tail (HT) and highly enantioselective, has long been overlooked in foregoing studies but is dominant in reality and is absolutely supramolecularly activated by 2:2 complexation of AC with β-CD. The intricate structural and photophysical aspects of this higher-order complexation-triggered process have been comprehensively elucidated, while the absolute configurations of the slipped cyclodimers have been unambiguously assigned by comparing the experimental and theoretical circular dichroism spectra. In the 2:2 complex, two ACs packed in a dual β-CD capsule are not fully overlapped with each other but are only partially stacked in a slipped <i>anti</i>- or <i>syn</i>-HT manner. Hence, they do not spontaneously cyclodimerize upon photoexcitation but instead emit long-lived excimer fluorescence at wavelengths slightly longer than the monomer fluorescence, indicating that the slipped excimer is neither extremely reactive nor completely relaxed in conformation and energy. Because of the slipped conformation of the AC pair in the soft capsule, the subsequent photocyclodimerization becomes manipulable by various internal or external factors, such as temperature, pressure, added salt, and host modification, enabling us to exclusively obtain the slipped cyclodimers with high regio- and enantioselectivities. In this supramolecularly driven photochirogenesis, the dual β-CD capsule functions as a chiral organophotocatalyst to trigger and accelerate the nonclassical photochirogenic route to slipped cyclodimers by preorganizing the conformation of the encapsulated AC pair, formally mimicking a catalytic antibody