Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors.

Natural glycosaminoglycans (GAGs) are arguably the most diverse collection of natural products. Unfortunately, this bounty of structures remains untapped. Decades of research has realized only one GAG-like synthetic, small-molecule drug, fondaparinux. This represents an abysmal output because GAGs present a frontier that few medicinal chemists, and even fewer pharmaceutical companies, dare to undertake. GAGs are heterogeneous, polymeric, polydisperse, highly water soluble, synthetically challenging, too rapidly cleared, and difficult to analyze. Additionally, GAG binding to proteins is not very selective and GAG-binding sites are shallow. This Perspective attempts to transform this negative view into a much more promising one by highlighting recent advances in GAG mimetics. The Perspective focuses on the principles used in the design/discovery of drug-like, synthetic, sulfated small molecules as allosteric modulators of coagulation factors, such as antithrombin, thrombin, and factor XIa. These principles will also aid the design/discovery of sulfated agents against cancer, inflammation, and microbial infection.

Practical Remdesivir Synthesis through One-Pot Organocatalyzed Asymmetric (S)-P-Phosphoramidation.

Remdesivir, an inhibitor of RNA-dependent RNA polymerase developed by Gilead Sciences, has been used for the treatment of COVID-19. The synthesis of remdesivir is, however, challenging, and the overall cost is relatively high. Particularly, the stereoselective assembly of the P-chirogenic center requires recrystallization of a 1:1 isomeric p-nitrophenylphosphoramidate mixture several times to obtain the desired diastereoisomer (39%) for further coupling with the d-ribose-derived 5-alcohol. To address this problem, a variety of chiral bicyclic imidazoles were synthesized as organocatalysts for stereoselective (S)-P-phosphoramidation employing a 1:1 diastereomeric mixture of phosphoramidoyl chloridates as the coupling reagent to avoid a waste of the other diastereomer. Through a systematic study of different catalysts at different temperatures and concentrations, a mixture of the (S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9 ratio when 20 mol % of the chiral imidazole-cinnamaldehyde-derived carbamate was utilized in the reaction at -20 °C. A 10-g scale one-pot synthesis via a combination of (S)-P-phosphoramidation and protecting group removal followed by one-step recrystallization gave remdesivir in 70% yield and 99.3/0.7 d.r. The organocatalyst was recovered in 83% yield for reuse, and similar results were obtained. This one-pot process offers an excellent opportunity for industrial production of remdesivir.

A Synthetic Strategy for the Construction of Functionalized Triphenylene Frameworks via Palladium Catalyzed Intramolecular Annulation/Decyanogenative C-H Bond Alkenylation.

The palladium catalyzed synthesis of 14-phenylbenzo[ f]tetraphene-9-carbonitrile derivatives as core polycyclic aromatic hydrocarbons (PAHs) was achieved via an intramolecular annulation and decyanogenative C-H bond alkenylation strategy. A readily synthesized Knoevenagel condensation product of [1,1'-biphenyl]-2,2'-dicarbaldehyde with benzyl cyanide converted successfully into 14-phenylbenzo[ f]tetraphene-9-carbonitrile derivatives in excellent yields up to 94%. The transformation involves an intramolecular cascade C-C bond formation along with a C-H bond cleavage sequence.

Synthesis of Polysubstituted Cyclopentene and Cyclopenta[ b]carbazole Analogues from Unsymmetrical 4-Arylidene-3,6-diarylhex-2-en-5-ynal and Indole Derivatives via an Iodine Mediated Electrocyclization Reaction.

An efficient method for the synthesis of polysubstituted cyclopentene and cyclopenta[ b]carbazole derivatives through the iodine-promoted electrocyclization of substituted indoles and 4-arylidene-3,6-diarylhex-2-en-5-ynal derivatives is reported. Polysubstituted cyclopentene derivatives were produced through 4π electrocyclization reactions with indole, 7-methylindole, and 5-bromoindole as coupling partners, whereas cyclopenta[ b]carbazole derivatives were produced via 6π electrocyclization in the case of methoxy (-OMe)-substituted indoles. The methods reported herein diastereo- and regioselectively proceed under straightforward and mild conditions.

Copper-Catalyzed Cascade Synthesis of 2-Aryl-3-cyanobenzofuran and Dibenzo[ b, f]oxepine-10-carbonitrile Derivatives.

The copper-catalyzed reaction of aryl aldehydes with 2-iodobenzylcyanides afforded 2-aryl-3-cyanobenzofurans in isolated yields of up to 74% in a cascade manner, which involves Knoevenagel condensation, aryl hydroxylation, oxa-Michael addition, and aromatization reactions. Conversely, 2-halo benzaldehydes as reacting partners with 2-iodobenzylcyanide regioselectively furnished dibenzo[ b,f]oxepine-10-carbonitrile derivatives up to 85% isolated yields via tandem Knoevenagel condensation, aryl hydroxylation, and Ullmann coupling reactions.