Bicyclic iminium ethers can be synthesized by the reactions of ketones with hydroxyalkyl azides. These cationic species react with a variety of nucleophiles via two possible pathways. The initially formed, kinetic product arises from direct addition to the iminium carbon in the substrate. In some cases, the initial adduct reverts to the starting iminium ether and the ultimate product arises from nucleophilic displacement at the O-alkyl group to afford the terminally functionalized N-substituted amide. The behavior of a range of nucleophiles was studied by using several iminium ethers. In general, the relevant pathway could be identified by characterization of the product formed. For hydroxide addition, which can afford only one product regardless of mechanism, the reaction was shown to arise by the kinetic pathway, using (18)O-labeled hydroxide. A one-pot synthesis of functionalized lactams entailing treatment of ketones first with hydroxyalkyl azides followed by nucleophilic addition was also developed.

The conversion of sterically hindered carboxylic acids to N-methoxy-N-methyl amides can be efficiently carried out with 1.1 equiv of methanesulfonyl chloride, 3 equiv of triethylamine, and 1.1 equiv of N-methoxy-N-methylamine. Yields for this process range from 59% to 88%. The major byproduct in these reactions, N-methoxy-N-methylmethanesulfonamide, can be removed by placing the product mixture under vacuum for 14-24 h.

A tandem Prins/Friedel-Crafts reaction useful for the construction of the indeno-tetrahydropyridine core of the haouamine alkaloids and a formal synthesis of (−)-haouamine A are described.

The parallel synthesis of gamma-turn-inspired peptidomimetic libraries has been demonstrated through two approaches toward the preparation of 1,4-diazepin-5-ones. In the first approach, 1,4-diazepin-5-ones scaffolds were prepared on gram scale and subsequently diversified to produce libraries. In a second approach, libraries of 1,4-diazepin-5-ones were produced directly through a three-component strategy that maximizes the diversity obtained in a single step.

The construction of a 225-member (3 × 5 × 15) library of thiadiazepan-1,1-dioxide-4-ones was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 184/225 sultams. Three sultam core scaffolds were prepared based upon the utilization of an aza-Michael reaction on a multifunctional vinyl sulfonamide linchpin. The library exploits peripheral diversity in the form of a sequential, twostep [3 + 2] Huisgen cycloaddition/Pd-catalyzed Suzuki-Miyaura coupling sequence.