Chiral Macrocyclic Catalysts for the Enantioselective Addition of Lithium Acetylides to Ketones.

Alkynyl addition to carbonyl compounds is a valuable synthetic method for the preparation of versatile chiral alcohols that are widely found in pharmaceuticals and natural products. Although a variety of enantioselective variations have been reported, alkynyl addition to simple ketones remains an unmet challenge due to their low reactivity and difficult enantiofacial discrimination. Here, we report a method for the catalytic enantioselective addition of lithium acetylide to a variety of ketones using macrocyclic lithium binaphtholates as catalysts. These reactions generally suffer from facile aggregation of lithium species, which leads to less active and selective catalysts. The macrocyclic structure designed in this study prevents such aggregation, affording a monomeric and highly active catalyst that can furnish enantioenriched tertiary alcohols from a variety of ketones within 5-30 min. Moreover, the confined cavity and lipophilicity of the macrocycle confer substrate specificity on the system, demonstrating a multiselectivity similar to that of enzymatic reactions. Thus, these findings offer new insights into the rational design of small-molecule artificial enzymes that exhibit high levels of reactivity and multiselectivity.

Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir.

We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the development of a concise and efficient scale-up process to Ensitrelvir. In this process, introducing a meta-cresolyl moiety successfully enhanced the stability of intermediates. Compared to the initial route at the early research and development stage, the overall yield of the longest linear sequence (6 steps) was improved by approximately 7-fold. Furthermore, 9 out of the 12 isolated intermediates were crystallized directly from each reaction mixture without any extractive workup (direct isolation). This led to an efficient and environmentally friendly manufacturing process that minimizes waste of organic solvents, reagents, and processing time. This practical process for manufacturing Ensitrelvir should contribute to protection against COVID-19.

Enantio- and Site-Selective α-Fluorination of N-Acyl 3,5-Dimethylpyrazoles Catalyzed by Chiral π-CuII Complexes.

Catalytic enantioselective α-fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α-fluorinated carbonyl compounds. Nevertheless, α-fluorination of α-nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pKa values of their α-hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3-(2-naphthyl)-l-alanine-derived amides are highly effective catalysts for the enantio- and site-selective α-fluorination of N-(α-arylacetyl) and N-(α-alkylacetyl) 3,5-dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α-fluorinated α-amino acid derivative). α-Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.

Understanding and Interrupting the Fischer Azaindolization Reaction.

Experimental and computational studies pertaining to the Fischer azaindolization reaction are reported. These studies explain why pyridylhydrazines are poorly reactive in Fischer indolization reactions, in addition to the origin of hydrazine substituent effects. Additionally, an interrupted variant of Fischer azaindolization methodology is disclosed, which provides a synthetic entryway into fused azaindoline scaffolds.

Enantioselective Cyanosilylation of Ketones with Lithium(I) Dicyanotrimethylsilicate(IV) Catalyzed by a Chiral Lithium(I) Phosphoryl Phenoxide.

A highly enantioselective cyanosilylation of ketones was developed by using a chiral lithium(I) phosphoryl phenoxide aqua complex as an acid/base cooperative catalyst. The pentacoordinate silicate generated in situ from Me3SiCN/LiCN acts as an extremely reactive cyano reagent. Described is a 30 gram scale reaction and the synthesis of the key precursor to (+)-13-hydroxyisocyclocelabenzine.