Inhibition of Kornblum Reaction with Lithium Salts in S2 Reactions of Sulfonates and a Nucleophile Containing a Pyridine -Oxide Moiety: Convergent and Selective Synthesis of an MRGPRX2 Antagonist.

A critical step in the development of a convergent synthesis of an MRGPRX2 antagonist () was the S2 reaction with a highly functionalized lactamide electrophile and a unique difluoropiperidine nucleophile containing a pyridine -oxide moiety. Initial reactions with sulfonate leaving groups exhibited superb stereoselectivity, but yields were very low due to side reactions originated from competitive Kornblum reactions of the pyridine -oxide and the sulfonates. Markedly improved reaction profiles were achieved by including stoichiometric lithium triflate.

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 SAr 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.

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.