Paul E. Floreancig

Oxidation-Resistant Fluorogenic Probe for Mercury Based on Alkyne Oxymercuration

Mercury continues to be a major safety hazard to the general public. Therefore, a fluorescence method that has potential for on-site use can be very useful. Most fluorescent probes for mercury are based on the interaction between mercury ions and sulfur atoms, which may not be compatible with mercury samples prepared by oxidation processes. Herein we report a fluorogenic probe for mercury based on the unique ability of Hg2+ to convert an alkyne to a ketone. By this methodology, the probe, prepared in two steps in 80% overall yield, is converted to a very bright green fluorescent molecule by Hg2+ in pH 7 buffer. This fluorescence method is sensitive, showing a signal-to-background ratio of 3 at 8 ppb mercury level, and highly specific for this metal ion. Since this detection method does not rely on mercury−heteroatom interactions, the probe is resistant to oxidants and thus can be used against mercury samples prepared by oxidative procedures. We demonstrate that our method can be applied to fish and dental...

Oxidative Carbocation Formation in Macrocycles: Synthesis of the Neopeltolide Macrocycle

Macrocyclic oxocarbenium ions can be formed from macrolactones that contain benzylic or allylic ether groups through oxidative carbon-hydrogen-bond activation mediated by 2,3-dichloro-4,5-dicyanoquinone (DDQ). The applicability of this efficient reaction to complex-molecule synthesis was demonstrated by its use in a brief formal synthesis of neopeltolide (see retrosynthetic scheme) to form the tetrahydropyrone ring.

Diastereoselective Tetrahydropyrone Synthesis through Transition‐Metal‐Free Oxidative Carbon–Hydrogen Bond Activation

Selectively activating chemical bonds that are generally considered to be inert is an attractive strategy for introducing functionality into and enhancing the structural complexity of easily-prepared substrates, particularly when bond activation ultimately leads to carbon–carbon bond formation. We have reported several examples in which oxidative carbon– carbon bond activation can be used to initiate cyclization reactions through carbon–carbon bond formation. Reaction initiation through single-electron oxidation alleviates chemoselectivity problems that can arise from conventional Lewis acid initiated methods for electrophile formation. To facilitate substrate synthesis and improve reaction atom economy we have initiated a program that is directed toward promoting oxidative electrophile formation by carbon–hydrogen bond activation. Toward this objective we initially chose to exploit the propensity of 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ) to form aryl-substituted oxocarbenium ions from benzylic ethers. This process has been utilized for bimolecular carbon–carbon bond formation, but these reactions proceed efficiently only with electron-rich arenes, and either require high temperatures with ketone nucleophiles or dicarbonyl/Lewis acid mixtures, or the addition of pregenerated nucleophiles such as enolsilanes after cation formation. Successful and broad application of DDQ-mediated carbon–hydrogen bond activation and subsequent carbon– carbon bond formation to annulation reactions requires that the nucleophiles be stable toward DDQ, that the reaction products not be subject to additional oxidation, and that a wide range of ethers serve as substrates. Herein we report that DDQ promotes the formation of stabilized carbocations by benzylic carbon–hydrogen bond activation under ambient conditions in the presence of appended nucleophilic groups and leads to diastereoselective carbon–carbon bond formation. Particularly important is the observation that, relative to bimolecular addition reactions, appending nucleophilic groups to the ether enhances the range of the benzylic groups that can serve as cation precursors. We also demonstrate that the scope of the process can be dramatically expanded by applying the protocol in an efficient approach to ring formation through allylic carbon–hydrogen bond activation. The incorporation of oxygen-containing groups into the substrates and the impact of arene or alkene substitution on the reaction rate is also discussed. Our initial studies focused on the conversion of paramethoxybenzyl (PMB) ether 1 into tetrahydropyrone 2 (Scheme 1) by DDQ-mediated oxocarbenium ion formation.

Highly Enantioselective Catalytic Cross-Dehydrogenative Coupling of N-Carbamoyl Tetrahydroisoquinolines and Terminal Alkynes

The first catalytic asymmetric cross-dehydrogenative coupling of cyclic carbamates and terminal alkynes has been established. The reaction features high enantiocontrol and excellent functional group tolerance and displays a wide range of structurally and electronically diverse carbamates as well as terminal alkynes. N-Acyl hemiaminals were identified as the reactive intermediates through preliminary control experiments. Employing readily removable carbamates as substrates rather than traditionally adopted N-aryl amines allows applications in complex molecule synthesis and therefore advances the C-H functionalization strategy to a synthetically useful level.

Structurally and stereochemically diverse tetrahydropyran synthesis through oxidative C-H bond activation.

Tetrahydropyrans are core units within a multitude of biologically active natural products, [1] and methods to prepare these structures, which utilize C–H bond functionalization as a prelude to C–C bond-formation are desirable. This approach is both step[2] and atom[3] economical, because the substrate preparation and reactive intermediate generation employ unreactive C–H bonds, rather than conventional leaving groups. We have shown that heterocycles can be formed with high levels of diastereocontrol from benzylic and allylic ethers through the DDQ-mediated (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) oxocarbenium ion formation, and subsequent intramolecular nucleophilic addition. [4] This method is highly complementary to Prins-based methods in the preparation of tetrahydropyrans, [5] and has been validated through its application to natural product synthesis. [6] Additional strategic benefits of this approach include the tolerance of acid labile functional groups towards oxidative conditions, [7] the application of facile etherification reactions to form stable linkages in segment coupling reactions, and the access to versatile unsaturated products. We have shown that this unsaturation provides a route towards a range of structurally and stereochemically diverse tetrahydropyrans through post-cyclization manipulations. Vinylsilane- and alkyne-containing products serve as useful moieties for application in target- and diversity-oriented synthesis.

Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs.

The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-Catalyzed Reactions Employing MnO2 as a Stoichiometric Oxidant

Several oxidative reactions can be effected with MnO(2) in the presence of substoichiometric quantities of DDQ. These transformations include oxidative cyclization, deprotection, and dehydrogenation reactions. The use of MnO(2) as a terminal oxidant for DDQ-mediated reactions is attractive based on economical and environmental factors.

Synthesis of Sulfur-Containing Heterocycles through Oxidative Carbon–Hydrogen Bond Functionalization

Vinyl sulfides react rapidly and efficiently with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to form α,β-unsaturated thiocarbenium ions through oxidative carbon-hydrogen bond cleavage. These electrophiles couple with appended π-nucleophiles to yield sulfur-containing heterocycles through carbon-carbon bond formation. Several nucleophiles are compatible with the procedure, and the reactions generally proceed through readily predictable transition states.

Stereoselective Synthesis of Tertiary Ethers through Geometric Control of Highly Substituted Oxocarbenium Ions

Oxocarbenium ions are intermediates in a number of synthetic processes including Prins cyclizations,[1] acid-mediated additions to acetals,[2] allyl group transfers,[3] and additions of carbonyls to electrophiles.[4] Stereocontrol in these transformations can be quite high as a result of the strong preference, calculated at approximately 2 kcalmol−1,[5] for monosubstituted oxocarbenium ions to exist in E configurations. However, reports of geometric control for 1,1-disubstituted oxocarbenium ions are rare[6] because the steric difference between the alkyl groups is generally smaller than the steric difference between an alkyl group and a hydrogen atom. General models that predict the geometry of disubstituted oxocarbenium ions would be valuable for designing syntheses of natural products or natural-product-like libraries[7] that contain tertiary ether groups. Recently, our research group reported[8] that intramolecular nucleophilic additions to alkynyl-substituted oxocarbenium ions proceed with minimal stereocontrol to provide cis- and trans-2,6-disubstituted tetrahydropyrans. This unusual lack of stereo-control results from the approximate energetic equivalence of the E and Z oxocarbenium ions, which is a result of the small steric difference between an alkynyl group and a hydrogen atom (Scheme 1). Herein, we describe a rare application of carbon–hydrogen bond functionalization for stereoselective syntheses of molecules that contain fully substituted carbon atoms. The approach is based on the development of a model that is able to predict the geometries of 1,1-disubstituted oxocarbenium ions involved in nucleophilic additions that form tertiary ethers with high stereocontrol. We also report a model that illustrates stereocontrol in intramolecular additions to monosubstituted oxocarbenium ions relative to a tertiary ether.

Cyclization Reactions through DDQ-Mediated Vinyl Oxazolidinone Oxidation

Vinyl oxazolidinones react with DDQ to form alpha,beta-unsaturated acyliminium ions in a new method for forming electrophiles under oxidative conditions. Appended nucleophiles undergo 1,4-addition reactions with these intermediates to form cyclic vinyl oxazolidinones with good levels of diastereocontrol, highlighting a new approach to utilizing oxidative carbon-hydrogen bond functionalization to increase molecular complexity.