Pt-Catalyzed Rearrangement of Oxaspirohexanes to 3‑Methylenetetrahydrofurans: Scope and Mechanism

A novel Pt-catalyzed rearrangement of oxaspirohexanes to 3-methylenetetrahydrofurans is reported. Mechanistic studies by ¹³C-labeling experiments confirm oxidative addition of Pt­(II) regioselectively to the least substituted carbon–carbon bond of the cyclopropane to form a platinacyclobutane intermediate. To our knowledge, this is the first alkoxy-substituted platinacyclobutane that has been observed spectroscopically. The scope and a proposed mechanism of this new Pt-catalyzed transformation are described

Toward a Formal Synthesis of Laureatin: Unexpected Rearrangements Involving Cyclic Ether Nucleophiles

Laureatin, a metabolite of the red algae <i>Laurencia nipponica</i>, has shown potent activity as a mosquito larvicide. The two previously published syntheses of laureatin involved an initial preparation of the 8-membered cyclic ether, followed by formation of the oxetane ring. Our strategy was the reverse, i.e., to utilize an oxetane as the framework to construct the larger ring. During this work, attempted <i>N</i>-bromosuccinimide (NBS)-mediated cyclization of oxetane alcohol <b>17</b>, prepared from readily accessible 2-methyleneoxetane <b>12</b>, yielded epoxytetrahydrofuran <b>19</b> rather than the expected laureatin core. Further derivatization of <b>19</b> yielded <i>trans</i> fused bis-tetrahydrofuran <b>32</b>. The synthesis of <b>19</b> and <b>32</b>, as well as structural and stereochemical elucidation studies, are described

Toward a Formal Synthesis of Laureatin: Unexpected Rearrangements Involving Cyclic Ether Nucleophiles

Laureatin, a metabolite of the red algae <i>Laurencia nipponica</i>, has shown potent activity as a mosquito larvicide. The two previously published syntheses of laureatin involved an initial preparation of the 8-membered cyclic ether, followed by formation of the oxetane ring. Our strategy was the reverse, i.e., to utilize an oxetane as the framework to construct the larger ring. During this work, attempted <i>N</i>-bromosuccinimide (NBS)-mediated cyclization of oxetane alcohol <b>17</b>, prepared from readily accessible 2-methyleneoxetane <b>12</b>, yielded epoxytetrahydrofuran <b>19</b> rather than the expected laureatin core. Further derivatization of <b>19</b> yielded <i>trans</i> fused bis-tetrahydrofuran <b>32</b>. The synthesis of <b>19</b> and <b>32</b>, as well as structural and stereochemical elucidation studies, are described

Rh-Catalyzed Conjugate Addition of Aryl and Alkenyl Boronic Acids to α‑Methylene-β-lactones: Stereoselective Synthesis of <i>trans</i>-3,4-Disubstituted β‑Lactones

A one-step preparation of 3,4-disubstituted β-lactones through Rh-catalyzed conjugate addition of aryl or alkenyl boronic acids to α-methylene-β-lactones is described. The operationally simple, stereoselective transformation provides a broad range of β-lactones from individual α-methylene-β-lactone templates. This methodology allowed for a direct, final-step C-3 diversification of nocardiolactone, an antimicrobial natural product

Pt-Catalyzed Rearrangement of Oxaspirohexanes to 3‑Methylenetetrahydrofurans: Scope and Mechanism

A novel Pt-catalyzed rearrangement of oxaspirohexanes to 3-methylenetetrahydrofurans is reported. Mechanistic studies by ¹³C-labeling experiments confirm oxidative addition of Pt­(II) regioselectively to the least substituted carbon–carbon bond of the cyclopropane to form a platinacyclobutane intermediate. To our knowledge, this is the first alkoxy-substituted platinacyclobutane that has been observed spectroscopically. The scope and a proposed mechanism of this new Pt-catalyzed transformation are described

Silicon Acceleration of a Tandem Alkene Isomerization/Electrocyclic Ring-opening of 2‑Methyleneoxetanes to α,β-Unsaturated Methylketones

The first rearrangement of 2-methyleneoxetanes to α,β-unsaturated methylketones is reported. It is proposed that when these substrates are heated, the corresponding oxetenes are formed and subsequently undergo electrocyclic ring-opening to methyl vinylketones. In particular, α-silyl-α,β-unsaturated methylketones were isolated in moderate to high yields and with high stereoselectivities. Based on the proposed mechanism, density functional theory explains the differential kinetics and stereoselectivities among substrates

DataSheet_1_A humanized mouse model for in vivo evaluation of invariant Natural Killer T cell responses.pdf

Invariant natural killer T (iNKT) cells mediate immune responses when stimulated by glycolipid agonists presented by CD1d. In extensive studies of synthetic analogues of α-galactosyl ceramides, we identified numerous examples of significant differences in the recognition of specific glycolipids in wild type mice versus human iNKT cell clones or PBMC samples. To predict human iNKT cell responses more accurately in a mouse model, we derived a mouse line in which compound genetic modifications were used to express a human-like iNKT cell TCR along with human CD1d in place of the endogenous mouse proteins. Detailed transcriptional and phenotypic profiling demonstrated that these partially humanized mice developed an expanded population of T cells recognizing CD1d-presented glycolipid antigens, among which a subset characterized by expression of chemokine receptor CXCR6 had features characteristic of authentic iNKT cells. Responses to iNKT cell activating glycolipids in these mice generated cytokine production in vitro and in vivo that showed a pattern of fine specificity that closely resembled that of cultured human iNKT cell clones. Anti-tumor responses to variants of α-galactosyl ceramide in VαKI mice also correlated with their potency for stimulating human iNKT cells. This genetically modified mouse line provides a practical model for human presentation and recognition of iNKT cell activators in the context of a normally functioning immune system, and may furnish valuable opportunities for preclinical evaluation of iNKT cell-based therapies.</p

Image_1_A humanized mouse model for in vivo evaluation of invariant Natural Killer T cell responses.tif

Invariant natural killer T (iNKT) cells mediate immune responses when stimulated by glycolipid agonists presented by CD1d. In extensive studies of synthetic analogues of α-galactosyl ceramides, we identified numerous examples of significant differences in the recognition of specific glycolipids in wild type mice versus human iNKT cell clones or PBMC samples. To predict human iNKT cell responses more accurately in a mouse model, we derived a mouse line in which compound genetic modifications were used to express a human-like iNKT cell TCR along with human CD1d in place of the endogenous mouse proteins. Detailed transcriptional and phenotypic profiling demonstrated that these partially humanized mice developed an expanded population of T cells recognizing CD1d-presented glycolipid antigens, among which a subset characterized by expression of chemokine receptor CXCR6 had features characteristic of authentic iNKT cells. Responses to iNKT cell activating glycolipids in these mice generated cytokine production in vitro and in vivo that showed a pattern of fine specificity that closely resembled that of cultured human iNKT cell clones. Anti-tumor responses to variants of α-galactosyl ceramide in VαKI mice also correlated with their potency for stimulating human iNKT cells. This genetically modified mouse line provides a practical model for human presentation and recognition of iNKT cell activators in the context of a normally functioning immune system, and may furnish valuable opportunities for preclinical evaluation of iNKT cell-based therapies.</p

A Humanized Mouse Model Coupled with Computational Analysis Identifies Potent Glycolipid Agonist of Invariant NKT Cells

Invariant natural killer T (iNKT) cells play an important role in many innate and adaptive immune responses, with potential applications in cancer immunotherapy. The glycolipid KRN7000, an α-galactosylceramide, potently activates iNKT cells but has shown limited anticancer effects in human clinical trials conducted so far. In spite of almost three decades of structure–activity relationship studies, no alternative glycolipid has yet emerged as a superior clinical candidate. One reason for the slow progress in this area is that standard mouse models do not accurately reflect the specific ligand recognition by human iNKT cells and their requirements for activation. Here we evaluated a series of KRN7000 analogues using a recently developed humanized mouse model that expresses a human αTCR chain sequence and human CD1d. In this process, a more stimulatory, previously reported but largely overlooked glycolipid was identified, and its activity was probed and rationalized via molecular simulations