A Sulfur-Controlled Approach to the Synthesis of Linerixibat.

Establishing the two stereocenters in the benzothiazepine ring of linerixibat (GSK2330672) has been a long-standing problem at GSK. Our solution rests on an episulfonium-controlled Ritter reaction followed by a sulfoxide-directed reduction. A rationale for both steps is based on a mixture of literature precedent and computational experiments. Transition state modeling suggests the sulfoxide-directed reduction proceeds through electronic repulsion between the lone pair of electrons on sulfur and the incoming borohydride anion.

Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis.

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.

Structurally dynamic hydrogels derived from 1,2-dithiolanes.

The design and generation of adaptable materials derived from structurally dynamic polymers provides a strategy for generating smart materials that can respond to environmental stimuli or exhibit self-healing behavior. Herein we report an expedient organocatalytic ring-opening polymerization of cyclic carbonates containing pendant dithiolanes (trimethylene carbonate/dithiolane, TMCDT) from poly(ethylene oxide) diols to generate water-soluble triblock (ABA) copolymers containing a central poly(ethylene oxide) block and terminal dithiolane blocks. Hydrogels generated from the triblock copolymers and a cross-linking dithiol exhibited dynamic behavior as a result of the reversible ring opening of the pendant 1,2-dithiolanes. These materials exhibit self-healing behavior, can be injected through a syringe, and rapidly recover their mechanical properties after a severe strain deformation. The dynamic properties of these gels can be modulated with the number of dithiolane units, pH, and temperature.

Origins of 1,6-stereoinduction in torquoselective 6π electrocyclizations.

A novel stereoselective electrocyclization developed for the total synthesis of reserpine has been explored by both experiment and theory. A stereocenter six atoms away from the newly forming chiral center is responsible for the diastereoselectivity of the ring closure. This stereogenic center, lying at the junction of two six-membered rings, defines the conformation of the substrates' fused ring skeleton that ultimately distinguishes between the two allowed, disrotatory triene geometries at the transition state. The presence of allylic strain in the disfavored transition state results in a torquoselective ring closure (dr up to 15.7:1).

A torquoselective 6π electrocyclization approach to reserpine alkaloids.

A highly torquoselective thermal triene 6π electrocyclization controls the relative stereochemistry between the C3 and C18 stereocenters of the dodecahydroindolo[2,3-a]benzo[g]quinolizine skeleton of reserpine-type alkaloids. Employing a tandem cross-coupling/electrocyclization protocol allowed us to form the requisite triene and ensure its subsequent cyclization. A novel low-temperature dibromoketene acetal Claisen rearrangement established the requisite exocyclic dienylbromide precursor for the palladium-catalyzed cross-coupling reaction.