Total Synthesis of (−)-Irciniastatin B and Structural Confirmation via Chemical Conversion to (+)-Irciniastatin A (Psymberin)

The total synthesis and structural confirmation of the marine sponge cytotoxin (−)-irciniastatin B has been achieved via a unified strategy employing a late-stage, selective deprotection/oxidation sequence that provides access to both (+)-irciniastatin A (psymberin) and (−)-irciniastatin B

The Design, Synthesis and Validation of Recoverable and Readily Reusable Siloxane Transfer Agents for Pd-Catalyzed Cross-Coupling Reactions

The development of competent, recoverable and reusable 1-oxa-2-silacyclopentene (siloxane) transfer agents for Pd-catalyzed cross-coupling reactions (CCRs) of organolithium reagents with aryl and alkenyl iodides has been achieved. Drawbacks of the first-generation siloxane-transfer agent (<b>1</b>), relating to facile recovery for potential recycling, have been addressed

The Design, Synthesis and Validation of Recoverable and Readily Reusable Siloxane Transfer Agents for Pd-Catalyzed Cross-Coupling Reactions

The development of competent, recoverable and reusable 1-oxa-2-silacyclopentene (siloxane) transfer agents for Pd-catalyzed cross-coupling reactions (CCRs) of organolithium reagents with aryl and alkenyl iodides has been achieved. Drawbacks of the first-generation siloxane-transfer agent (<b>1</b>), relating to facile recovery for potential recycling, have been addressed

Total Synthesis of (+)-Irciniastatin A (a.k.a. Psymberin) and (−)-Irciniastatin B

A unified synthetic strategy to access (+)-irciniastatin A (a.k.a. psymberin) and (−)-irciniastatin B, two cytotoxic secondary metabolites, has been achieved. Highlights of the convergent strategy comprise a boron-mediated aldol union to set the C(15)–C(17) <i>syn–syn</i> triad, reagent control to set the four stereocenters of the tetrahydropyran core, and a late-stage Curtius rearrangement to install the acid-sensitive stereogenic <i>N</i>,<i>O</i>-aminal. Having achieved the total synthesis of (+)-irciniastatin A, we devised an improved synthetic route to the tetrahydropyran core (13 steps) compared to the first-generation synthesis (22 steps). Construction of the structurally similar (−)-irciniastatin B was then achieved via modification of a late-stage (−)-irciniastatin A intermediate to implement a chemoselective deprotection/oxidation sequence to access the requisite oxidation state at C(11) of the tetrahydropyran core. Of particular significance, the unified strategy will permit late-stage diversification for analogue development, designed to explore the biological role of substitution at the C(11) position of these highly potent tumor cell growth inhibitory molecules

Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents

The design, synthesis, and biological evaluation of irciniastatin A (<b>1</b>) analogues, achieved by removal of three synthetically challenging structural units, as well as by functional group manipulation of the C(11) substituent of both irciniastatins A and B (<b>1</b> and <b>2</b>), has been achieved. To this end, we first designed a convergent synthetic route toward the diminutive analogue (+)-<i>C</i>(8)-desmethoxy-<i>C</i>(11)-deoxy-<i>C</i>(12)-didesmethylirciniastatin (<b>6</b>). Key transformations include an acid-catalyzed 6-<i>exo</i>-tet pyran cyclization, a chiral Lewis acid mediated aldol reaction, and a facile amide union. The absolute configuration of <b>6</b> was confirmed via spectroscopic analysis (CD spectrum, HSQC, COSY, and ROESY NMR experiments). Structure–activity relationship (SAR) studies of <b>6</b> demonstrate that the absence of the three native structural units permits access to analogues possessing cytotoxic activity in the nanomolar range. Second, manipulation of the C(11) position, employing late-stage synthetic intermediates from our irciniastatin syntheses, provides an additional five analogues (<b>7</b>–<b>11</b>). Biological evaluation of these analogues indicates a high functional group tolerance at position C(11)

Facile Route to 2‑Fluoropyridines via 2‑Pyridyltrialkylammonium Salts Prepared from Pyridine <i>N</i>‑Oxides and Application to ¹⁸F‑Labeling

Among known precursors for 2-[¹⁸F]­fluoropyridines, pyridyltrialkylammonium salts have shown excellent reactivity; however, their broader utility has been limited because synthetic methods for their preparation suffer from poor functional group compatibility. In this paper, we demonstrate the regioselective conversion of readily available pyridine <i>N</i>-oxides into 2-pyridyltrialkylammonium salts under mild and metal-free conditions. These isolable intermediates serve as effective precursors to structurally diverse 2-fluoropyridines, including molecules relevant to PET imaging. In addition to providing access to nonradioactive analogues, this method has been successfully applied to ¹⁸F-labeling in the radiosynthesis of [¹⁸F]­AV-1451 ([¹⁸F]­T807), a PET tracer currently under development for imaging tau

Brain-Penetrant, Orally Bioavailable Microtubule-Stabilizing Small Molecules Are Potential Candidate Therapeutics for Alzheimer’s Disease and Related Tauopathies

Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer’s disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administration and the inhibition of the P-glycoprotein (Pgp) transporter. Thus, the identification of alternative CNS-active MT-stabilizing agents that lack these potential limitations is of interest. Toward this objective, we have evaluated representative compounds from known classes of non-naturally occurring MT-stabilizing small molecules. This led to the identification of selected triazolopyrimidines and phenylpyrimidines that are orally bioavailable and brain-penetrant without disruption of Pgp function. Pharmacodynamic studies confirmed that representative compounds from these series enhance MT-stabilization in the brains of wild-type mice. Thus, these classes of MT-stabilizers hold promise for the development of orally active, CNS-directed MT-stabilizing therapies