Minh H. Nguyen

Total Synthesis of (−)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol

Anion relay chemistry (ARC), an effective, multicomponent union tactic, was successfully employed for the total synthesis of the highly cytotoxic marine macrolide (−)-mandelalide A (1). The northern hemisphere was constructed via a new type II ARC/CuCN cross-coupling tactic, while the southern hemisphere was secured via a highly efficient four-component type I ARC union. Importantly, the synthesis of 1 showcases ARC as a rapid, scalable coupling strategy for the union of simple readily available building blocks to access diverse complex molecular fragments with excellent stereochemical control.

The iron-catalyzed construction of 2-aminopyrimidines from alkynenitriles and cyanamides.

Several cycloaddition catalysts and reagents were surveyed for their effectiveness toward cyclizing alkynenitriles with cyanamides. Catalytic amounts of FeI2, (iPr)PDAI and Zn were found to effectively catalyze the [2+2+2] cycloaddition of a variety of cyanamides and alkynenitriles to afford bicyclic 2-aminopyrimidines.

Polymer-supported siloxane transfer agents for Pd-catalyzed cross-coupling reactions.

The design, synthesis, and validation of a ring-opening metathesis polymerization (ROMP) polymer supporting siloxane transfer agents have been achieved that permit efficient palladium-catalyzed cross-coupling reactions. The solubility properties of the polymer facilitate not only product purification but also polymer recycling without significant loss of cross-coupling activity.

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 (1), relating to facile recovery for potential recycling, have been addressed.

Recyclable polystyrene-supported siloxane-transfer agent for palladium-catalyzed cross-coupling reactions.

The rational design, synthesis, and validation of a significantly improved insoluble polymer-supported siloxane-transfer agent has been achieved that permits efficient palladium-catalyzed cross-coupling reactions. The cross-linked polystyrene support facilitates product purification with excellent siloxane recycling. Drawbacks of a previous polymer-supported siloxane-transfer agent, relating to reaction efficiency and polymer stability after repeated cycles, have been addressed.

Regioselective Iron-Catalyzed [2 + 2 + 2] Cycloaddition Reaction Forming 4,6-Disubstituted 2-Aminopyridines from Terminal Alkynes and Cyanamides

Iron complexes bound by redox-active pyridine dialdimine (PDAI) ligands catalyze the cycloaddition of two terminal alkynes and one cyanamide. The reaction is both chemo- and regioselective, as only 4,6-disubstituted 2-aminopyridine products are formed in moderate to high yields. Isolation of an iron azametallacycle (4) suggests that catalyst deactivation occurs with a large excess of cyanamide over longer reaction times. Fe-catalyzed cycloaddition allowed for a straightforward synthesis of a variety of aminopyridines, including known estrogen receptor ligands.

New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors

Mandelalides A-D (1-4) are macrocyclic polyketides known to have an unusual bioactivity profile influenced by compound glycosylation and growth phase of cultured cells. The isolation and characterization of additional natural congeners, mandelalides E-L (5-12), and the supply of synthetic compounds 1 and 12, as well as seco-mandelalide A methyl ester (13), have now facilitated mechanism of action and structure-activity relationship studies. Glycosylated mandelalides are effective inhibitors of aerobic respiration in living cells. Macrolides 1 and 2 inhibit mitochondrial function similar to oligomycin A and apoptolidin A, selective inhibitors of the mammalian ATP synthase (complex V). 1 inhibits ATP synthase activity from isolated mitochondria and triggers caspase-dependent apoptosis in HeLa cells, which are more sensitive to inhibition by 1 in the presence of the glycolysis inhibitor 2-deoxyglucose. Thus, mandelalide cytotoxicity depends on basal metabolic phenotype; cells with an oxidative phenotype are most likely to be inhibited by the mandelalides.

Design, Synthesis, and Application of Polymer-Supported Silicon-Transfer Agents for Cross-Coupling Reactions with Organolithium Reagents

The initial design, synthesis, and validation of polymer-supported siloxane transfer agents have been achieved that permit the direct use of organolithium reagents in the palladium-catalyzed cross-coupling reactions. Through rational design, two generations of polymer support were developed that significantly simplify product purification and the transfer agent recycling.

Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy

The mandelalides comprise a family of structurally complex marine macrolides that display significant cytotoxicity against several human cancer cell lines. Presented here is a full account on the development of an Anion Relay Chemistry (ARC) strategy for the total synthesis of (-)-mandelalides A and L, the two most potent members of the mandelalide family. The design and implementation of a three-component type II ARC/cross-coupling protocol and a four-component type I ARC union permits rapid access respectively to the key tetrahydrofuran and tetrahydropyran structural motifs of these natural products. Other highlights of the synthesis include an osmium-catalyzed oxidative cyclization of an allylic 1,3-diol, a mild Yamaguchi esterification to unite the northern and southern hemispheres, and a late-stage Heck macrocyclization. Synthetic mandelalides A and L displayed potent cytotoxicity against human HeLa cervical cancer cells (EC50, 1.3 and 3.1 nM, respectively). This synthetic approach also provides access to several highly potent non-natural mandelalide analogs, including a biotin-tagged mandelalide probe for future biological investigation.