RESUMO
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.
RESUMO
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.
Assuntos
Antivirais/farmacologia , Boratos/farmacologia , Ácidos Borônicos/farmacologia , Paládio/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Boratos/síntese química , Boratos/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Catálise , Estrutura Molecular , Proteínas não Estruturais Virais/metabolismoRESUMO
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.
Assuntos
Furanos/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Isoquinolinas/síntese química , Poríferos/química , Animais , Ciclização , EstereoisomerismoRESUMO
[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.
Assuntos
Carbolinas/síntese química , Carbolinas/química , Cristalografia por Raios X , Iminas/síntese química , Conformação Molecular , Estrutura MolecularRESUMO
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.