Synthesis and Evaluation of Azolium-Based Halogen-Bond Donors.

A method for the synthesis of iodinated imidazolium and triazolium N-heterocyclic halogen-bond-donor catalysts has been developed. This approach was applied to the synthesis of a variety of 1,2,4-triazolium salts to prepare a series of novel chiral halogen-bond-donor catalysts. The counterions of the iodinated triazoliums can be readily exchanged with chiral and achiral non-coordinating counterions to produce unique scaffolds. Their ability to promote/catalyse a conjugate addition reaction with indole was investigated. Through these initial studies, a set of general guidelines and considerations for the application of these halogen-bond donors in organocatalysis have been established.

Enantioselective Synthesis of Indolines, Benzodihydrothiophenes, and Indanes by C-H Insertion of Donor/Donor Carbenes.

We employ a single catalyst/oxidant system to enable the asymmetric syntheses of indolines, benzodihydrothiophenes, and indanes by C-H insertion of donor/donor carbenes. This methodology enables the rapid construction of densely substituted five-membered rings that form the core of many drug targets and natural products. Furthermore, oxidation of hydrazones to the corresponding diazo compounds proceeds in situ, enabling a relatively facile one- or two-pot protocol in which isolation of potentially explosive diazo alkanes is avoided. Regioselectivity studies were performed to determine the impact of sterics and electronics in donor/donor metal carbene C-H insertions to form indolines. This methodology was applied to a variety of substrates in high yield, diastereomeric, and enantiomeric ratios and to the synthesis of a patented indane estrogen receptor agonist with anti-cancer activity.

Synthesis of Benzodihydrofurans by Asymmetric C-H Insertion Reactions of Donor/Donor Rhodium Carbenes.

Metal carbenes appended with two electron-donating groups, known as "donor/donor" carbenes, undergo diastereo- and enantioselective rhodium-catalyzed C-H insertion reactions with ether substrates to form benzodihydrofurans. Unlike the reactions of metal carbenes with electron-withdrawing groups attached, the attenuated electrophilicity enables these reactions to be conducted in Lewis basic solvents (e.g., acetonitrile) and in the presence of water. The diazo precursors for these species are prepared in situ from hydrazone using a mild and chemoselective oxidant (MnO2 ). Although this sequence often can be performed in one-pot, control experiments have elucidated why a "two-pot" process is often more efficient. A thorough screening of achiral catalysts demonstrated that sterically encumbered catalysts are optimal for diastereoselective reactions. Although efficient insertion into allylic and propargylic C-H bonds is observed, competing dipolar cycloaddition processes are noted for some substrates. The full substrate scope of this useful method of benzodihydrofuran synthesis, mechanisms of side reactions, and computational support for the origins of stereoselectivity are described.

Synthesis of Esters by in Situ Formation and Trapping of Diazoalkanes.

A general method has been developed for the in situ formation and trapping of diazoalkanes by carboxylic acids to form esters. The method is applicable to a large variety of carboxylic acids using diazo compounds that are formed from the hydrazones of benzaldehydes and aryl ketones. In situ reaction monitoring with IR spectroscopy (ReactIR) was used to demonstrate that slow addition of the hydrazone to a mixture of oxidant and carboxylic acid avoids the buildup of the diazo compound. This method enables the safe preparation of esters from simple precursors without isolation of diazo compounds.

Enantioselective intramolecular C-H insertion reactions of donor-donor metal carbenoids.

The first asymmetric insertion reactions of donor-donor carbenoids, i.e., those with no pendant electron-withdrawing groups, are reported. This process enables the synthesis of densely substituted benzodihydrofurans with high levels of enantio- and diastereoselectivity. Preliminary results show similar efficiency in the preparation of indanes. This new method is used in the first enantioselective synthesis of an oligoresveratrol natural product (E-δ-viniferin).