Fe-Catalyzed Structurally Divergent γ-Polyhaloalkylation of Siloxydienes.

Regioselective γ-polyhaloalkylation is achieved using tetrahalomethanes or α,α,α-trihaloalkyl compounds and siloxydienes via Fe(II) catalysis. A range of siloxydienes are functionalized in good yields with high stereoselectivity under mild reaction conditions. Structural divergence is observed as either haloalkylated or haloalkenylated products are formed on the basis of the substitution pattern of the siloxydiene.

Remote Fluorination of α,β-Unsaturated Carbonyls via Silyl Dienol Ethers.

We report a general, regioselective, and metal free γ-fluorination of α,β-unsaturated carbonyls via silyl dienol ethers that are readily prepared from simple ketones and aldehydes. The transformation displays broad scope including 27 cyclic and acyclic siloxydienes providing γ-fluoro compounds in 28-91 % yield. Notably, the reported conditions are also suitable for the synthesis of challenging tertiary fluorides.

Iron-Catalyzed Gamma-Gamma Dimerization of Siloxydienes.

We report the oxidative dimerization reaction of siloxydienes derived from simple enones that creates a new gamma-gamma (γ-γ) C-C bond using catalytic iron and benzoyl peroxide as the terminal oxidant in acetonitrile solvent at ambient temperature. The reaction shows a broad substrate scope including cyclic and acyclic siloxydienes derived from ketones, aldehydes, and esters, which are converted to 1,8-dicarbonyl compounds under mild catalytic reaction conditions in 19-89 % yield across 30 examples. The method is suitable for the coupling of sterically demanding carbon centers, including the formation of vicinal quaternary centers.

DBDA Matrix Increases Ion Abundance of Fatty Acids and Sulfatides in MALDI-TOF and Mass Spectrometry Imaging Studies.

MALDI-TOF MS is a powerful tool to analyze biomolecules, owing to its soft ionization nature that generally results in simple spectra of singly charged ions. Implementation of the technology in the imaging mode provides a means to spatially map analytes in situ. Recently, a new matrix, DBDA (1,4-dibenzylidenebenzene-1,4-diamine) was reported to facilitate the ionization of free fatty acids in negative ion mode.

DBDA matrix increases ion abundance of fatty acids and sulfatides in MALDI-TOF and mass spectrometry imaging studies.

MALDI-TOF MS is a powerful tool to analyze biomolecules owing to its soft ionization nature and generally results in simple spectra of singly charged ions. Moreover, implementation of the technology in imaging mode provides a means to spatially map analytes in situ. Recently, a new matrix, DBDA (N1,N4-dibenzylidenebenzene-1,4-diamine) was reported to facilitate the ionization of free fatty acids in the negative ion mode.

Total Synthesis of Benzofuran-Based Aspergillusene B via Halogenative Aromatization of Enones.

A novel "non-aromatic pool" synthetic strategy for the synthesis of benzofuran-based natural products via oxidative haloaromatization of enones is reported. This approach is successfully applied in the first total synthesis of the natural product aspergillusene B. In comparison with a separately executed "aromatic pool" synthesis, the "non-aromatic pool" protocol demonstrates equivalent efficiency but offers a much higher degree of modularity.

Short Enantioselective Formal Synthesis of (-)-Platencin.

A short enantioselective formal synthesis of the antibiotic natural product platencin is reported. Key steps in the synthesis include enantioselective decarboxylation alkylation, aldehyde/olefin radical cyclization, and regioselective aldol cyclization.

Enantioconvergent catalysis.

An enantioconvergent catalytic process has the potential to convert a racemic starting material to a single highly enantioenriched product with a maximum yield of 100%. Three mechanistically distinct approaches to effecting enantioconvergent catalysis are identified, and recent examples of each are highlighted. These processes are compared to related, non-enantioconvergent methods.

Total Synthesis of Grifolin, Grifolic Acid, LL-Z1272α, LL-Z1272β, and Ilicicolinic Acid A.

A novel synthetic approach for the synthesis of bioactive phenolic natural products is reported. This strategy highlights the power of halogenative aromatization reactions recently developed in our group for preparing densely functionalized arenes in a controlled fashion. Five natural products related by an aromatic core and a farnesyl side chain are synthesized.

Regiocontrolled Oxidative C-C Coupling of Dienol Ethers and 1,3-Dicarbonyl Compounds.

A strategy for synthesis of γ-alkylated enones through oxidative coupling of siloxydienes and 1,3-dicarbonyl compounds is reported. This method is an interrupted form of our formal [3 + 2] cycloaddition method reported previously. The present work excels in generating all-carbon quaternary centers via C-C bond formation at the remote γ-site which is traditionally challenging to functionalize.

Cu-Catalyzed Stereoselective γ-Alkylation of Enones.

A general regio- and stereoselective γ-C-C bond formation is achieved using α-halocarbonyl compounds and dienol ethers via Cu(II) catalysis. This method constitutes a novel approach to the challenging 1,6-dioxygenation motif. A range of γ-substituted enones, including many bearing all-carbon quaternary centers, are available through a simple protocol under mild reaction conditions with superb functional group compatibility.

Direct Regioselective γ-Amination of Enones.

Carbonyl compounds bearing a γ-amino group are valuable pharmacologically active targets. Regioselective γ-C-N bond formation is achieved with simple enone substrates through controlled dienolate reactivity toward azodicarboxylate electrophiles. The amination reaction occurs readily with sterically demanding nucleophiles and is stereoselective.

Cascade Mn-Mediated γ-Alkylation/oxa-Michael Addition of Enones with 1,3-Dicarbonyls.

A radical-based strategy for regioselective γ-C-C bond formation/oxa-conjugate addition, forming the tetrahydrobenzofuran core common to many bioactive natural products is described. The technique utilizes readily available enone derivatives and 1,3-dicarbonyl compounds as coupling partners in an oxidative formal [3+2] cycloaddition mediated by Mn(III) . The transformation delivers polycyclic products in good yields and proceeds with complete regiocontrol and excellent stereoselectivity.

Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones.

The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee's up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.

Copper-Catalyzed γ-Sulfonylation of α,β-Unsaturated Carbonyl Compounds by Means of Silyl Dienol Ethers.

A regioselective method for the introduction of sulfonyl groups at the γ-carbon of enone systems is reported. Using a copper catalyst and readily available sulfonyl chlorides, a range of silyl dienol ethers are sulfonylated in good yield under mild reaction conditions. The sulfone derivatives formed are poised for further synthetic manipulations as demonstrated by regioselective alkylations.

Regiodivergent halogenation of vinylogous esters: one-pot, transition-metal-free access to differentiated haloresorcinols.

We report an efficient method for the regiodivergent synthesis of halogenated resorcinol derivatives using readily available vinylogous esters and sulfonyl halide halogen donors. Either the 4- or 6-haloresorcinol isomer is accessible from a common precursor. In contrast to conventional oxidants for arene halogenation, mild sulfonyl halides allow broad functional group compatibility.

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation.

Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of "classic" natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge.

The reaction mechanism of the enantioselective Tsuji allylation: inner-sphere and outer-sphere pathways, internal rearrangements, and asymmetric C-C bond formation.

We use first principles quantum mechanics (density functional theory) to report a detailed reaction mechanism of the asymmetric Tsuji allylation involving prochiral nucleophiles and nonprochiral allyl fragments, which is consistent with experimental findings. The observed enantioselectivity is best explained with an inner-sphere mechanism involving the formation of a 5-coordinate Pd species that undergoes a ligand rearrangement, which is selective with regard to the prochiral faces of the intermediate enolate. Subsequent reductive elimination generates the product and a Pd(0) complex.

Competitive activity-based protein profiling identifies aza-β-lactams as a versatile chemotype for serine hydrolase inhibition.

Serine hydrolases are one of the largest and most diverse enzyme classes in Nature. Most serine hydrolases lack selective inhibitors, which are valuable probes for assigning functions to these enzymes. We recently discovered a set of aza-β-lactams (ABLs) that act as potent and selective inhibitors of the mammalian serine hydrolase protein-phosphatase methylesterase-1 (PME-1).

Enantioselective decarboxylative alkylation reactions: catalyst development, substrate scope, and mechanistic studies.

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity.

Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors.

National Institutes of Health (NIH)-sponsored screening centers provide academic researchers with a special opportunity to pursue small-molecule probes for protein targets that are outside the current interest of, or beyond the standard technologies employed by, the pharmaceutical industry. Here, we describe the outcome of an inhibitor screen for one such target, the enzyme protein phosphatase methylesterase-1 (PME-1), which regulates the methylesterification state of protein phosphatase 2A (PP2A) and is implicated in cancer and neurodegeneration. Inhibitors of PME-1 have not yet been described, which we attribute, at least in part, to a dearth of substrate assays compatible with high-throughput screening.

Enantioselective protonation.

Enantioselective protonation is a common process in biosynthetic sequences. The decarboxylase and esterase enzymes that effect this valuable transformation are able to control both the steric environment around the proton acceptor (typically an enolate) and the proton donor (typically a thiol). Recently, several chemical methods to achieve enantioselective protonation have been developed by exploiting various means of enantiocontrol in different mechanisms.