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We report a combined photocatalytic and hydrogen atom transfer (HAT) approach for the light-mediated epimerization of readily accessible piperidines to provide the more stable diastereomer with high selectivity. The generality of the transformation was explored for a large variety of di- to tetrasubstituted piperidines with aryl, alkyl, and carboxylic acid derivatives at multiple different sites. Piperidines without substitution on nitrogen as well as N-alkyl and aryl derivatives were effective epimerization substrates. The observed diastereoselectivities correlate with the calculated relative stabilities of the isomers. Demonstration of reaction reversibility, luminescence quenching, deuterium labeling studies, and quantum yield measurements provide information about the mechanism.

We report a photoredox-catalyzed α-amino C-H arylation reaction of highly substituted piperidine derivatives with electron-deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. To probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used to investigate the reaction. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer processes associated with radical formation beyond the initial excited-state Ir(ppy)3 oxidation. Following the rapid and unselective C-H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a majority of the products. Several stereoisomerically pure products were resubjected to the reaction conditions, each of which converged to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermodynamic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).

Multisubstituted tropanes and indolizidines have been prepared with high regio- and stereoselectivity by the [3+2] cycloaddition of unstabilized azomethine ylides generated from readily prepared trimethylsilyl-substituted 1,2-dihydropyridines via protonation or alkylation followed by desilylation. Starting from 1,2-dihydropyridines bearing a ring trimethylsilyl substituent at the 6-position, an intermolecular alkylation/desilylation provides endocyclic unstabilized ylides that successfully undergo cycloaddition with a range of symmetrical and unsymmetrical alkyne and alkene dipolarophiles to afford densely substituted tropanes incorporating quaternary carbons in good yields and with high regio- and stereoselectivity. Additionally, an intramolecular alkylation/desilylation/cycloaddition sequence provides convenient and rapid entry to bridged tricyclic tropane skeletons, allowing for five contiguous carbon stereocenters to be set in a single experimental operation and under mild conditions. Starting from 1,2-dihydropyridines with trimethylsilylmethyl groups on nitrogen, protonation followed by desilylation generates exocyclic unstabilized ylides that undergo cycloaddition with unsymmetrical alkynes to give indolizidines with good regio- and stereoselectivity. N-Trimethylsilylmethyl-1,2-dihydropyridines can also be alkylated and subsequently desilylated to give endocyclic unstabilized ylides that undergo intermolecular cycloadditions with carbonyl compounds to give bicyclic oxazolidine products in good overall yields. Moreover, an intramolecular alkylation/desilylation/cycloaddition sequence with the N-trimethylsilylmethyl-1,2-dihydropyridines affords tricyclic indolizidines that incorporate quaternary carbons and up to five stereocenters with good to excellent regio- and diastereoselectivity.

The first asymmetric intermolecular addition of non-acidic C-H bonds to imines is reported. The use of the activating N-perfluorobutanesulfinyl imine substituent is essential for achieving sufficient reactivity and provides outstanding diastereoselectivity (>98:2 dr). Straightforward removal of the sulfinyl group with HCl yields the highly enantiomerically enriched amine hydrochlorides.

We report formal [3 + 3] annulations of aromatic azides with aromatic imines and azobenzenes to give acridines and phenazines, respectively. These transformations proceed through a cascade process of Rh(III)-catalyzed amination followed by intramolecular electrophilic aromatic substitution and aromatization. Acridines can be directly prepared from aromatic aldehydes by in situ imine formation using catalytic benzylamine.

A practical, functional group tolerant method is described for the Rh-catalyzed direct arylation of a variety of pharmaceutically important azoles with aryl bromides. This new method has expanded the scope of heterocycle and aryl bromide coupling partners and has allowed assembly of the reactions without the need for glovebox or reagent purification.

Evidence for a proposed mechanism of C-H activation of 3-methyl-3,4-dihydroquinazoline by (PCy3)(sub 2)RhCl is presented. The consequences of the mechanism for coupling reactions of N-heterocycles that occur through Rh-catalyzed C-H bond activation are discussed.

A general method is described for asymmetric synthesis of both syn- and anti-1,3-amino alcohols. This method is found to be effective for a variety of substrates incorporating either aromatic or various aliphatic substituents.

A new synthetic method for peptide-alphathioesters is reported based on Fmoc-based SPPS.

Research is presented describing the solid-phase synthesis of cysteine protease inhibitors which are ketone-based. The fully substituted ketone products occur in 40-100% overall yields after they are released from the support by transformations and cleavage.

The experimental procedures for the parallel synthesis of medium-ring heterocyclic beta-turn mimetics are described. The innovative method involves the rapid generation of libraries of mimetics for the identification of small molecule ligands to receptors. The method has been applied to the synthesis of mimetics with a wide range of amino acid side chains. The development of the 87 nM ligand, a human somatotropin receptor 5, is also described.

A method for the solid-phase synthesis of aspartyl protease inhibitors that do not incorporate any amino acids is presented. Several potent small molecule inhibitors were identified when a library of 204 spatially separate prepared compounds were screened against cathepsin D. The solid-phase synthesis approach was found to be capable of rapidly identifying small molecule inhibitors to diverse aspartyl protease targets.

A study was conducted to characterize the catalytic asymmetric oxidation of tert-butyl disulfide. Reaction parameters were defined for the highly catalytic asymmetric oxidation of tert-butyl disulfide. Results indicated that enantiomerically pure thiosulfinate ester stereospecifically reacts with grignard reagents, lithium amides, lithium imine salts and organolithiums to produce pure chiral sulfoxides, sulfinimines and sulfinamides.

An approach is described to obtain a complete analysis of protease specificity using microarrays of peptidyl coumarin substrates. These arrays are constructed using standard DNA microarraying equipment, using aldehyde-derivatized glass slides and alkoxylamine-functionaliized peptidyl coumarin substrates.

A ruthenium-catalyzed, redox neutral C-O bond cleavage of 2-aryloxy-1-arylethanols is developed to obtain cleavage products in 62-98% isolated yield. Initial mechanistic study results indicated that the ether cleavage is most likely an organometallic C-O activation while a catalytic depolymerization of a lignin-related polymer quantitatively yields the corresponding monomer with no added reagent.

The article presents a new methodology, which uses alcohol as the reducing agent for carrying out catalytic didehydroxylation of vicinal diols to alkenes. The approach is shown to be extremely beneficial for the production of unsaturated compounds from the biomass-derived materials.

A T4 lysozome mutant possessing a peculiar 13C-labeled alanine is prepared based on the ability to isotopically label a single amino acid residue in a protein with unnatural amino acids. Unnatural amino acids are substituted at positions 20, 82 and 133 if TL4 to investigate the effects of side-chain and backbone structure on protein stability and catalytic activity. Thus, Ala 82 is replaced with (13C)alanine, with the mutant protein produced by in vitro suppression of an Ala 82 -> TAG nonsense mutation.

The highly enantioselective addition of thioacetic acid to nitroalkenes is described by using a new sulfinyl urea organocatalyst. The new method is used for preparing chiral 1,2-aminothiol derivatives, as shown by the first enantioselective synthesis of the clinically used antifungal drug sulconazole.

The Rh(I)-catalyzed addition of alkenylboron reagents to imines is described. The new method has enabled the efficient asymmetric synthesis of the important class of [alpha]-branched allylic amines from stable starting materials.

Rh(I)-catalyzed strategy is developed for the direct arylation of pyridines and quinolines. The heterocycle is without the requirement for prefunctionalization and the strategy has represented a new way to an important class of substituted heterocycles.

The article discusses a new approach, which uses N-tert-butanesulfinyl aldimines for the asymmetric copper-catalyzed synthesis of [alpha]-amino boronate esters. The method is shown to be extremely effective, as it gives high yields with high diastereoselectivities.

The substrate activity screening (SAS) method is employed for the identification of potent nonpeptidic inhibitors of cruzain. The discussed inhibitor is shown to possess the ability of leading to new chemotherapeutics for the treatment of Chagas disease.

A new approach using an intramolecular alkylation of an olefinic C-H bond catalyzed by Rh for the asymmetric synthesis of (-)-incarvillateine is discussed. The method is shown to be extremely stable and high-yielding.

A convenient one-pot C-H alkenylation/electrocyclization/aromatization sequence is developed for the synthesis of highly substituted pyridine derivatives from alkynes and [alpha],[beta]-unsaturated N-benzyl aldimines and ketimines that has proceeded through dihydropyridine intermediates. The Copasi software is used for determining rate constants for the transformation, which has implicated facile C-H oxidative addition and slow reductive elimination steps.

A new class of organocatalysts is developed that has incorporated the N-sulfinyl urea substituent, which is acidifying and serves as a chiral controlling element. The effectiveness of this organocatalyst is shown by catalysis of the aza-Henry reaction with high selectivity, which includes the examples of enantioselective H-bonding-catalyzed additions to aliphatic N-Boc imines.

The fragment-based substrate activity screening method for the identification of potent inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB) is being discussed. The small size of the compound imparts good selectivity to it.

A method is developed for the Rh(I)-catalyzed alkylation of pyridines and quinolines. The steric interaction from ortho-substituent has increased the equilibrium from an N-bound to a C-bound Rh complex.

The total synthesis of tubulysin D was accomplished in 13% overall yield over 16 steps for the longest linear sequence. The synthetic route allows access to all of the naturally occurring rubulysin derivates and truncated analogues and enables the synthesis of most of the stereoisomers of tubulysin D by appropriate selection of tert-butanesulfinamide stereochemistry for the synthesis of Tup and Tuv.

The successful execution of a useful and fundamentally new approach is reported for the first direct stereoselective synthesis of several classes of functionalized tri- and tetrasubstituted alpha,beta-unsaturated aldehydes. It was envisioned that the generality of the olefinic C-H activation could be broadened considerably by the alkylation of alpha,beta-unsaturated aldiminesm, which after hydrolysis would provide the corresponding alpha,beta-unsaturated aldehydes as versatile synthetic intermediates.

The first total synthesis of (+)-lithospermic acid is reported using asymmetric intramolecular alkylation through rhodium-catalyzed C-H bond activation. The first example of employing a chiral nonracemic imine as a directing group in a C-H bond activation method is presented.

The highly diastereoselctive addition of arylboronic acids to both aromatic and aliphatic N-tert-butanesulfinyl imines as well as the initial disclosure of the highly enantioselective addition of aylboronic acids to N-diphenylphosphinoyl benzaldimine is reported. Two new highly practical methods for the asymmetric synthesis of alpha-branched amines are developed.

A highly enantioselective and efficient method is developed for the intramolecular imine-directed C-H/olefin coupling reaction using chiral phosphoramidite ligands. The exceptional rates and enantioselectives observed using the phosphoramidite ligands may be due to their unique binding properties, which include reduced sigma donation to rhodium and enhanced pie acceptor ability compared to phosphines.

The covalent tail-to-tail dimers of vancomycin and the corresponding dimers of damaged vancomycin have similarly high antibacterial activity against VRE. The close structural resemblance and similar activities between the damaged and intact dimers shows that the antibacterial activity of the intact vancomycin dimers is likely to be due to mechanisms that do not involve L-Lys-D-Ala-D-Lac binding.

The intermediacy of an N-heterocyclic carbene(super 2) Rh(I) complex in the intermolecular coupling of an alkene to a benzimidazole core (eq 1)(super 3) is examined in the course of developing C-H activation processes. The intermolecular coupling became possible after it was discovered that weak acids dramatically increase the rate of both the inter- and intramolecular region.

The Rh-catalyzed C-H activation of alkyne-tethered [alpha],[beta]-unsaturated imines, followed by reaction of the activated intermediate with alkynes, is described. This activation has led to an intermediate that has undergone further thermal, electrocyclization to form strained bicyclic enamines with bridgehead unsaturated.

A new and efficient synthetic route was developed for the generation of the potent kinase inhibitor where intramolecular alkylation via rhodium-catalyzed C-H bond activation was the most important step. This approach allowed introduction of substituents at the C7 and C8 positions and evaluation of the compounds synthesized by this route made possible the identification of a JNK3 inhibitor.

The highly diastereoselective alpha-alkylation of N'-tert-butanesulfinyl amidines is developed along with methods for converting the alkylation products to enantiomerically enriched amines that incorporate both alpha and beta stereocenters. The first asymmetric synthesis of (6R,7S)-7 amino-7,8-dihydro-alpha-bisabolene showed that this method should provide an efficient asymmetric synthesis of a wide variety of amine-containing compounds.

Catalytic enantioselective synthesis of sulfinate esters through dynamic resolution of racemic tert-butanesulfinyl chloride is presented. To achieve a catalytic enantioselective synthesis of sulfinate esters by sulfinyl transfer, a nucleophilic catalysis approach was chosen in the presence of a stoichiometric amine base that would consume the liberated HC1 byproduct of the sulfinyl transfer reaction.

The stereoselective synthesis of both the syn- and anti-1,3-amino alcohols from a common synthetic intermediate is depicted. The first application of metalloenamines derived from N-sulfinyl imines is reported for the highly diastereoselective addition to aldehydes.

The cooperative use of experiment and theory has led to the discovery of a novel carbene insertion mechanism in the intramolecular coupling of an alkene to a benzimidazole. An N-heterocyclic carbene complex was found to be the resting state of the catalyst, and the carbene insertion was calculated to be the rate-limiting step of the reaction.

Research was conducted to identify synthetic receptors targeting vancomycin-resistant bacteria through the use of a combinatorial library technique. Split synthesis was used to prepare a library of 39,304 theoretical members. The most active library members were detected by an on bead assay while library screening was carried out with 5 mM vancomycin. Results demonstrate remarkable selectivity and significantly increased binding to N-Ac2-L-Lys-D-Ala-D-Lac which show that the tripeptide portion contributes substantially to the binding interaction.