Nathan K. Yee

Organometallic methods for the synthesis and functionalization of azaindoles

Azaindoles (also called pyrrolopyridines) constitute essential subunits in many pharmaceutically important compounds. The synthesis of azaindoles has been a great synthetic challenge for chemists. Many classical methods for indole synthesis (such as Fischer and Madelung cyclizations) often cannot be effectively applied to the synthesis of the corresponding azaindoles. In recent years, advances in organometallic chemistry have enabled a number of novel and efficient methodologies for azaindole formation as well as for the further functionalization of azaindole templates. In this tutorial review, we have surveyed the recent development of organometallic chemistry-based methods for azaindole synthesis.

Copper Catalyzed Asymmetric Propargylation of Aldehydes

The highly enantio- and regioselective copper catalyzed asymmetric propargylation of aldehydes with a propargyl borolane reagent is reported. The methodology demonstrated broad functional group tolerance and provided high enantioselectivities for aliphatic, vinyl, and aryl aldehydes. The utility of the TMS homopropargylic alcohols was demonstrated by the facile conversion to a chiral dihydropyranone.

Efficient Chiral Monophosphorus Ligands for Asymmetric Suzuki–Miyaura Coupling Reactions

A series of novel P-chiral monophosphorus ligands exhibit efficiency in asymmetric Suzuki-Miyaura coupling reactions, enabling the construction of an array of chiral biaryl products in high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. The carbonyl-benzooxazolidinone moiety in these chiral biaryl products allows facile derivatization for further synthetic applications. A computational study has revealed that a π-π interaction between the two coupling partners can enhance the enantioselectivity of the coupling reaction.

Efficient Monophosphorus Ligands for Palladium-Catalyzed Miyaura Borylation

In combination with the Bedford Pd precursor, the new biaryl monophosphorus ligand 5 was efficient for palladium-catalyzed Miyaura borylation of sterically hindered aryl bromides at low catalyst loadings.

Room Temperature Palladium-Catalyzed Cross Coupling of Aryltrimethylammonium Triflates with Aryl Grignard Reagents

Aryltrimethylammonium triflates and tetrafluoroborates were found to be highly reactive electrophiles in the Pd-catalyzed cross coupling with aryl Grignard reagents. The coupling reactions proceed at ambient temperature with a nearly stoichiometric quantity of Grignard reagent, and diverse functionality is tolerated. Competition experiments established the reactivity of PhNMe(3)OTf relative to PhCl, PhBr, PhI, and PhOTf.

RCM macrocyclization made practical: an efficient synthesis of HCV protease inhibitor BILN 2061.

We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.

Novel, Tunable, and Efficient Chiral Bisdihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation

A series of novel, efficient, air-stable, and tunable chiral bisdihydrobenzooxaphosphole ligands (BIBOPs) were developed for rhodium-catalyzed hydrogenations of various functionalized olefins such as alpha-arylenamides, alpha-(acylamino)acrylic acid derivatives, beta-(acylamino)acrylates, and dimethyl itaconate with excellent enantioselectivities (up to 99% ee) and reactivities (up to 2000 TON).

Mechanistic studies on the chiral recognition of polysaccharide-based chiral stationary phases using liquid chromatography and vibrational circular dichroism Reversal of elution order of N-substituted alpha-methyl phenylalanine esters

Enantiomeric separation of two aromatic alpha-substituted alanine esters was achieved on two commercially available polysaccharide-based chiral stationary phases (CSPs): amylose tris(3,5-dimethylphenylcarbamate) (ADMPC) and cellulose tris(3,5-dimethylphenylcarbamate) (CDMPC). The interactions between enantiomeric analytes and the CSPs were investigated using chromatographic methods and vibration circular dichroism (VCD). The two analytes differ on the aromatic portion of the molecules where one analyte has a pi-acceptor aromatic ring (1) while the other has a pi-donor aromatic ring (2). When an ADMPC CSP was employed, an increase in the polarity of the mobile phase leads to a reversal of the elution order for the two enantiomers of 1. The elution order of compound 2 was not affected by the polarity of the mobile phase. In order to gain an understanding of these phenomena, the enantiomeric separation of 1 and 2 was also performed on the CDMPC CSP. Interestingly, no reversal of elution order was observed upon the chromatographic separation of both pairs of enantiomers of compounds 1 and 2 upon increasing the solvent polarity when a CDMPC CSP was utilized. To understand the underlying mechanism governing these chiral separations, VCD was applied to study the structure of the ADMPC and CDMPC polymers and their conformational behaviors under chromatographic conditions. For the first time the conformations of the side chains of both polymers were revealed based on the VCD spectra along with DFT calculations. Furthermore, the interactions between the two analytes and the two CSPs were directly probed by VCD. By comparing the spectral differences of the two CSPs in the presence of the two analytes, the detailed interactions involving different functional groups associated with the chiral recognition were elucidated and thus explained the unusual reversal of elution order associated with increasing solvent polarity.

Synthesis of 1-aryl-1H-indazoles via the palladium-catalyzed cyclization of N-aryl-N′-(o-bromobenzyl)hydrazines and [N-aryl-N′-(o-bromobenzyl)-hydrazinato-N′]-triphenylphosphonium bromides

1-Aryl-1H-indazoles were synthesized by the palladium-catalyzed intramolecular amination [Pd(OAc)2/dppf/tBuONa (150 mol%)/toluene/90°C] of the corresponding N-aryl-N′-(o-bromobenzyl)hydrazines. It was further demonstrated that cyclization of [N-aryl-N′-(o-bromobenzyl)-hydrazinato-N′]-triphenylphosphonium bromides under the conditions of [Pd(OAc)2/dppf/tBuONa (250 mol%)/dioxane/90°C] also led to the formation of the corresponding 1-aryl-1H-indazoles. These methods were applied to a group of representative substrates to give indazole products in moderate to very good yields.

Copper-catalyzed annulation of 2-formylazoles with o-aminoiodoarenes.

In the presence of catalytic CuI and sparteine, 2-formylpyrroles can be annulated with o-aminoiodoarenes to give substituted pyrrolo[1,2-a]quinoxalines and related heterocycles. The reaction also works for annulation of 2-formylindoles, 2-formylimidazole, 2-formylbenzimidazole, and a 3-formylpyrazole.