Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

The frondosins are a family of marine sesquiterpenes isolated from the sponge Dysidea frondosa that exhibit biological activities ranging from anti-inflammatory properties to potential application in anticancer and HIV therapy. Herein, a concise enantioselective total synthesis of (+)-frondosin B is described which requires a total of three chemical steps. The enantioselective conjugate addition of a benzofuran-derived boronic acid to crotonaldehyde in the presence of an imidazolidinone organocatalyst builds the critical stereogenic center of frondosin B in the first operation, while the remaining two ring systems of this natural product are installed in the two subsequent steps. A combination of X-ray crystallographic data, deuterium labeling, and chemical correlation studies provides further evidence as to the correct absolute stereochemical assignment of (+)-frondosin B.

A novel palladium(II)-catalyzed oxy-carbopalladation process was developed allowing for the orchestrated union of hydroxy ynones with ethyl acrylate, two electron-deficient reactants. With beta-hydroxy ynones, this cascade Wacker-Heck process gave access to highly functionalized tri- or tetrasubstituted dihydropyranones featuring an unusual dienic system. For diastereomerically pure and for enantioenriched beta-hydroxyynones, these reactions proceed without affecting the stereochemical integrity of the existing stereocenters. In addition, tetrasubstituted furanones can be prepared when alpha-hydroxyynones and ethyl acrylate are used as starting materials. The dihydropyranones and furanones obtained upon cyclization are novel compounds, but structurally related carbohydrate derivatives featuring a similar dienic system have been used as starting materials for the construction of polyannulated products, suggesting that these cascade Pd(II)-mediated oxidative heterocyclizations are of value for various synthetic applications.

[reaction: see text] A palladium(II)-mediated oxidative cyclization was found to be effective for the preparation of structurally diverse 2,3-dihydro-4H-pyran-4-ones from the corresponding beta-hydroxyenones. Attractive features of this transformation include the ready availability of the starting enones, the regiocontrol, and the easy access of enantiopure 2,3-dihydro-4H-pyran-4-one from the corresponding enantiopure enone.

A conceptually novel approach to hetero Diels-Alder adducts of carbonyl compounds is described using as the key steps an antibody-mediated kinetic resolution of hydroxyenones followed by a ring-closure process. Various beta-hydroxyenones proved to be very good substrates for antibodies 84G3- and 93F3-catalyzed retro-aldol reactions, allowing the preparation of highly enantiomerically enriched (up to 99% ee) precursors of pyranones. An attractive feature of this methodology is the possibility to convert these acyclic-enantioenriched beta-hydroxyenones into tetrahydropyranones by a conventional Michael-type addition procedure or into the corresponding dihydropyranones using an alternative palladium-catalyzed oxidative ring closure. For the palladium-mediated cyclization, a biphasic system has been implemented that allows the direct preparation of enantiopure dihydropyranones from the corresponding racemic aldol precursors using a sequential antibody-resolution/palladium-cyclization strategy, without isolation of the intermediate enantioenriched hydroxyenones. This bioorganic route is best applied to the preparation of hetero Diels-Alder adducts otherwise derived from less nucleophilic dienes and unactivated dienophiles.