Anti-selective [3+2] (Hetero)annulation of non-conjugated alkenes via directed nucleopalladation.

2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tolerates a wide variety of functional groups.

Development of a Late-Stage Diversification Strategy for the 4- and 5-Positions of 4,5,6-Trisubstituted Indazoles.

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles.

An enzymatic Alder-ene reaction.

An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organocatalysts or transition metal catalysts to control stereoselectivity, regioselectivity and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases-a family of enzymes that catalyse pericyclic reactions.

Rhodium(III)-Catalyzed C-H Activation: Ligand-Controlled Regioselective Synthesis of 4-Methyl-Substituted Dihydroisoquinolones.

Rh-catalyzed C-H functionalization of -pivaloyl benzhydroxamic acids with propene gas provides access to 4-methyl-substituted dihydroisoquinolones. Good to excellent levels of regioselectivity are achieved using [CpRhCl] as a precatalyst under optimized conditions. Thorough examination of aryl/heteroaryl -pivaloyl hydroxamic acid substrates, ligand effects on C-H site selectivity, alkene scope, and demonstration of scale are discussed within.

Cyclic Alkyne Approach to Heteroatom-Containing Polycyclic Aromatic Hydrocarbon Scaffolds.

We report a modular synthetic strategy for accessing heteroatom-containing polycyclic aromatic hydrocarbons (PAHs). Our approach relies on the controlled generation of transient heterocyclic alkynes and arynes. The strained intermediates undergo in situ trapping with readily accessible oxadiazinones.

Diels-Alder cycloadditions of strained azacyclic allenes.

For over a century, the structures and reactivities of strained organic compounds have captivated the chemical community. Whereas triple-bond-containing strained intermediates have been well studied, cyclic allenes have received far less attention. Additionally, studies of cyclic allenes that bear heteroatoms in the ring are scarce.

Synthesis of 8-Hydroxygeraniol.

An operationally simple protocol for the conversion of geranyl acetate to 8-hydroxygeraniol is reported. The convenient two-step procedure relies on an efficient, chemo- and regioselective SeO-promoted oxidation, followed by straightforward deacetylation. This facile means to prepare 8-hydroxygeraniol is expected to enable biosynthetic studies pertaining to thousands of monoterpene indole alkaloids.

Engineering the biocatalytic selectivity of iridoid production in Saccharomyces cerevisiae.

Monoterpene indole alkaloids (MIAs) represent a structurally diverse, medicinally essential class of plant derived natural products. The universal MIA building block strictosidine was recently produced in the yeast Saccharomyces cerevisiae, setting the stage for optimization of microbial production. However, the irreversible reduction of pathway intermediates by yeast enzymes results in a non-recoverable loss of carbon, which has a strong negative impact on metabolic flux.

Enzyme-Catalyzed Intramolecular Enantioselective Hydroalkoxylation.

Hydroalkoxylation is a powerful and efficient method of forming C-O bonds and cyclic ethers in synthetic chemistry. In studying the biosynthesis of the fungal natural product herqueinone, we identified an enzyme that can perform an intramolecular enantioselective hydroalkoxylation reaction. PhnH catalyzes the addition of a phenol to the terminal olefin of a reverse prenyl group to give a dihydrobenzofuran product.

Nitrone Cycloadditions of 1,2-Cyclohexadiene.

We report the first 1,3-dipolar cycloadditions of 1,2-cyclohexadiene, a rarely exploited strained allene. 1,2-Cyclohexadiene is generated in situ under mild conditions and trapped with nitrones to give isoxazolidine products in synthetically useful yields. The reactions occur regioselectively and exhibit a notable endo preference, thus resulting in the controlled formation of two new bonds and two stereogenic centers.