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.

Total synthesis of (±)-cortistatin J from furan.

A concise, diastereoselective total synthesis of (±)-cortistatin J has been completed in 20 steps from furan. Key steps include an intramolecular [4 + 3] cyclization of a disubstituted furan with a (Z)-2-(trialkylsilyloxy)-2-enal to construct the tetracyclic core and a (Z)-vinylsilane/iminium ion cyclization to form the A ring.

Total synthesis of (-)-nakadomarin A.

A concise diastereoselective total synthesis of (-)-nakadomarin A has been completed in 21 steps from D-pyroglutamic acid. Key steps include an enecarbamate Michael addition/furan-N-acyliminium ion cascade cyclization to provide the tetracyclic core and ring-closing alkyne and alkene metatheses to construct the fifteen- and eight-membered azacycles, respectively.

Generation of N-acyliminium ions via intramolecular conjugate addition reactions: a strategy for the total synthesis of nakadomarin A.

[reaction: see text] The rapid construction of the tetracyclic core ring system of nakadomarin A via a tandem enecarbamate Michael addition/N-acyliminium ion cyclization is described.