Seth B. Herzon

Room temperature, palladium-mediated P-arylation of secondary phosphine oxides.

We show that a broad range of aryl iodides are efficiently coupled with secondary phosphine oxides using 1 mol % of a catalyst formed in situ from tris(dibenzylideneacetone)dipalladium and Xantphos (1). Scalemic (S)-methylphenylphosphine oxide [(S)-2e] is shown to undergo arylation without detectable stereoerosion. The application of this method to the synthesis of novel P-chiral phosphines and PCP ligands is demonstrated.

A method for the selective hydrogenation of alkenyl halides to alkyl halides.

A general method for the selective hydrogenation of alkenyl halides to alkyl halides is described. Fluoro, chloro, bromo, iodo, and gem-dihaloalkenes are viable substrates for the transformation. The selectivity of the hydrogenation is consistent with reduction by a hydrogen atom transfer pathway.

The cytotoxicity of (−)-lomaiviticin A arises from induction of double-strand breaks in DNA

The metabolite (–)-lomaiviticin A, which contains two diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups, inhibits the growth of cultured human cancer cells at nanomolar–picomolar concentrations; however, the mechanism responsible for the potent cytotoxicity of this natural product is not known. Here we report that (–)-lomaiviticin A nicks and cleaves plasmid DNA by an ROS- and iron-independent pathway and that the potent cytotoxicity of (–)-lomaiviticin A arises from induction of DNA double-strand breaks (dsbs). In a plasmid cleavage assay, the ratio of single-strand breaks (ssbs) to dsbs is 5.3±0.6:1. Labeling studies suggest this cleavage occurs via a radical pathway. The structurally related isolates (–)-lomaiviticin C and (–)-kinamycin C, which contain one diazofluorene, are demonstrated to be much less effective DNA cleavage agents, thereby providing an explanation for the enhanced cytotoxicity of (–)-lomaiviticin A compared to other members of this family.

A robust and scalable synthesis of the potent neuroprotective agent (−)-huperzine A

(−)-Huperzine A (1) is a tricyclic alkaloid that is produced in low yield by the Chinese herb Huperzia serrata. There is intense contemporary interest in clinical application of (−)-huperzine A (1) for treating neurodegenerative diseases and protecting against the lethal effects of chemical warfare agents, such as sarin and VX. We report a robust, scalable, and efficient synthesis of (−)-huperzine A (1) from (R)-4-methyl-cyclohex-2-ene-1-one (5). Our route proceeds in 35–45% overall yield, delivers (−)-huperzine A (1) in only eight steps from cyclohexenone 5, requires only three chromatographic purifications, and can provide gram quantities of the target. This route represents a critical, enabling advance toward detailed evaluation of (−)-huperzine A (1) in clinical settings.

A Highly Active and Air-Stable Ruthenium Complex for the Ambient Temperature Anti-Markovnikov Reductive Hydration of Terminal Alkynes

The conversion of terminal alkynes to functionalized products by the direct addition of heteroatom-based nucleophiles is an important aim in catalysis. We report the design, synthesis, and mechanistic studies of the half-sandwich ruthenium complex 12, which is a highly active catalyst for the anti-Markovnikov reductive hydration of alkynes. The key design element of 12 involves a tridentate nitrogen-based ligand that contains a hemilabile 3-(dimethylamino)propyl substituent. Under neutral conditions, the dimethylamino substituent coordinates to the ruthenium center to generate an air-stable, 18-electron, κ(3)-complex. Mechanistic studies show that the dimethylamino substituent is partially dissociated from the ruthenium center (by protonation) in the reaction media, thereby generating a vacant coordination site for catalysis. These studies also show that this substituent increases hydrogenation activity by promoting activation of the reductant. At least three catalytic cycles, involving the decarboxylation of formic acid, hydration of the alkyne, and hydrogenation of the intermediate aldehyde, operate concurrently in reactions mediated by 12. A wide array of terminal alkynes are efficiently processed to linear alcohols using as little as 2 mol % of 12 at ambient temperature, and the complex 12 is stable for at least two weeks under air. The studies outlined herein establish 12 as the most active and practical catalyst for anti-Markovnikov reductive hydration discovered to date, define the structural parameters of 12 underlying its activity and stability, and delineate design strategies for synthesis of other multifunctional catalysts.

Development of a Convergent Entry to the Diazofluorene Antitumor Antibiotics: Enantioselective Synthesis of Kinamycin F

We describe a 12-step enantioselective synthetic route to the complex anticancer antimicrobial agent kinamycin F (3). Key to the success of the route was the development of a three-step sequence for construction of the diazonapthoquinone (diazofluorene, blue in structure 3) function of the natural product. This sequence comprises fluoride-mediated coupling of a beta-(trimethylsilylmethyl)-cyclohexenone and halonapthoquinone, palladium-mediated cyclization to construct the tetracyclic scaffold of the natural product, and mild diazo-transfer to a complex cyclopentadiene to introduce the diazo function. Ortho-quinone methide intermediates, formed by reduction and loss of dinitrogen from 3, have been postulated to form in vivo, and our approach provides a straightforward synthetic pathway to such compounds.

Regioselective Reductive Hydration of Alkynes To Form Branched or Linear Alcohols

The regioselective reductive hydration of terminal alkynes using two complementary dual catalytic systems is described. Branched or linear alcohols are obtained in 75-96% yield with ≥25:1 regioselectivity from the same starting materials. The method is compatible with terminal, di-, and trisubstituted alkenes. This reductive hydration constitutes a strategic surrogate to alkene oxyfunctionalization and may be of utility in multistep settings.

Intermolecular Hydropyridylation of Unactivated Alkenes

A general method for the hydropyridylation of unactivated alkenes is described. The transformation connects metal-mediated hydrogen atom transfer to alkenes and Minisci addition reactions. The reaction proceeds under mild conditions with high site-selectivities and allows for the construction of tertiary and quaternary centers from simple alkene starting materials.

Synthesis of the Fully Glycosylated Cyclohexenone Core of Lomaiviticin A

We describe two four-step sequences for conversion of the inexpensive reagent ethyl sorbate to either O-allyl-N,N-dimethyl-D-pyrrolosamine or O-allyl-L-oleandrose, protected forms of the 2,6-dideoxy sugar residues found in the complex bacterial metabolite lomaiviticin A. We also report a gram-scale synthesis of the highly-oxygenated cyclohexenone ring of this metabolite, and show this may be coupled with the aforementioned donors to form the bis(glycoside) 6. The longest linear sequence to 6 is nine steps.

Temporal separation of catalytic activities allows anti-Markovnikov reductive functionalization of terminal alkynes

There is currently great interest in the development of multistep catalytic processes in which one or several catalysts act sequentially to rapidly build complex molecular structures. Many enzymes—often the inspiration for new synthetic transformations—are capable of processing a single substrate through a chain of discrete, mechanistically distinct catalytic steps. Here, we describe an approach to emulate the efficiency of these natural reaction cascades within a synthetic catalyst by the temporal separation of catalytic activities. In this approach, a single catalyst exhibits multiple catalytic activities sequentially, allowing for the efficient processing of a substrate through a cascade pathway. Application of this design strategy has led to the development of a method to effect the anti-Markovnikov (linear-selective) reductive functionalization of terminal alkynes. The strategy of temporal separation may facilitate the development of other efficient synthetic reaction cascades. Multifunctional catalysts typically process substrates and intermediates concurrently. Here, a strategy is described to separate catalytic activities in the time domain (temporal separation). Application of this strategy has led to the development of a method to effect the anti-Markovnikov reductive functionalization of terminal alkynes; such an approach may facilitate the development of other synthetic reaction cascades.